Minimizing agglomeration, aeration, and preserving the coating of pharmaceutical compositions comprising ibuprofen

ABSTRACT

Provided are pharmaceutical compositions and methods for preparing pharmaceutical compositions comprising Ibuprofen using solventless mixing methods. Excess coating material that is not bound to coated Ibuprofen may be removed by a sieving process. Coating and dosing ratios can also be optimized to minimize the amount of excess unbound coating material. Additionally, the compositions can be formulated to preserve the functional coating of coated Ibuprofen and to minimize aeration of Ibuprofen when mixed into suspension.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/008,108, filed Aug. 31, 2020, which is a continuation of U.S.application Ser. No. 16/798,130, filed Feb. 21, 2020, which claims thepriority of U.S. Provisional Application Nos. 62/809,307; 62/809,287;and 62/809,293, each filed Feb. 22, 2019, the entire contents of each ofwhich are incorporated herein by reference.

FIELD

This relates to processes for coating Ibuprofen, and more particularly,to processes that minimize excess coating material to preventagglomeration of the coated Ibuprofen in a lyophilized orallydisintegrating dosage form during storage, processes that minimizeaeration of pharmaceutical suspensions comprising Ibuprofen for improveddose weight accuracy whilst maintaining the integrity of the functionalcoat on the Ibuprofen, and processes that preserve the coating of coatedIbuprofen produced by solventless mixing processes and formulated todelay release of the Ibuprofen upon oral administration.

BACKGROUND

Pharmaceutical compositions typically include both an activepharmaceutical ingredient as well as one or more inactive ingredients.The active pharmaceutical ingredient (API) is biologically active and isdesigned to directly affect a patient's symptoms, diseases, disorders,and/or ailments. One example of an active pharmaceutical ingredient isIbuprofen. The inactive ingredient(s) of a pharmaceutical composition,on the other hand, are pharmaceutically inert and can be used forvarious purposes including, but not limited to, improving long-termstabilization, filling or diluting a solid formulation, facilitatingdrug absorption, modifying viscosity of liquid formulations, enhancingsolubility and/or aiding the manufacture of the pharmaceuticalcomposition.

In addition, some inactive ingredients may be used to mask the taste ofthe API, such as Ibuprofen. Many APIs are known to exhibit unpleasantorganoleptic properties if allowed to dissolve in the oral cavity, suchas bitter taste, burning sensation and numbing. For example, someorally-administered pharmaceutical compositions are designed to dispersein the mouth to enable administration without water and are targeted topediatric patients, geriatric patients, animal patients, and/or othertypes of patients that may have difficulties swallowing. For these typesof orally-administered pharmaceutical compositions, an inactiveingredient may be used to form a “functional coating” to mask the tasteof the API, or Ibuprofen.

For example, an inactive ingredient may be used to mask the taste of theAPI by wet coating or dry coating the API particle to produce afunctional coating surrounding the API particle such that it preventsAPI release in the mouth. In wet particle coating, inactive ingredients(polymer and additives) are dissolved or dispersed in solvent or waterto form a suspension or solution. This suspension or solution can thenbe sprayed onto the surface of the API particle to form a coating offilm by evaporation of the solvent or water. Examples of technologiesfor wet particle coating include microencapsulation, fluid bed coating,spray drying, pan coating etc. In dry particle coating (also referred toas solventless coating), API particles are physically coated with fineparticles of inactive ingredients (polymer and additives) to formparticle composites. Examples of dry particle coating include hot meltcoating, supercritical coating, impaction coating, electrostaticcoating. API particles coated with a taste-masking inactive ingredientmay provide a more pleasant experience for a patient having difficultiesswallowing or having a sensitivity to taste that would otherwise lead toa negative patient experience and poor compliance.

Additionally, one type of pharmaceutical composition is anorally-disintegrating tablet (ODT). ODTs are pharmaceutical compositionstargeted to pediatric patients, geriatric patients, animal patients,and/or other types of patients that may have difficulties swallowing.

To accurately dispense a pharmaceutical composition into a small,administrable form, a hydrophobic coated API particle can be placed in amatrix solution/suspension to form a pharmaceutical suspension. Mixingto form a pharmaceutical suspension allows for improved dosing accuracy.Oftentimes, this pharmaceutical suspension comprising the hydrophobiccoated API particles can be dosed into molds, dried, and the moldedarticle can then be transferred into a bottle, for example. However,this kind of handling of the pharmaceutical composition can increaserisks such as damage and contamination.

Accordingly, many API suspensions today are dosed into preformed blisterpacks instead. Preformed blister packs eliminate one of the handlingsteps described above. Instead of dosing into a mold and thentransferring the molded article to a bottle for packaging, preformedblister packs allow a manufacturer to dose the pharmaceutical suspensioninto a preformed blister pack that can be dried, then sealed andpackaged. Thus, the preformed blister pack serves as both the mold andthe package in which the pharmaceutical composition can be stored.

SUMMARY

Provided are methods for minimizing agglomeration of coating materialfor coated Ibuprofen produced using various mixing processes.Agglomeration of coating material can decrease the stability of thepharmaceutical product over time. For example, a pharmaceuticalproduct's disintegration time may increase over time if it comprisesagglomerated coating material. An increased disintegration times and/ora decreased dissolution rate implies an unstable pharmaceutical product.An unstable pharmaceutical product can lead to a shorter shelf life thandesired. Accordingly, embodiments provided may help minimizeagglomeration of coating material for coated Ibuprofen to improve thestability of the pharmaceutical product during storage and to increaseits shelf life.

For example, methods described include removing excess coating materialfrom the coated Ibuprofen to minimize the possibility of agglomerationof the coating material particles. Particularly, methods providedinclude sieving the coated Ibuprofen such that the final pharmaceuticalproduct is adequately surrounded by dry matrix, minimizing anyagglomeration of coating material particles upon storage. Pharmaceuticalcompositions described provide for a disintegration time and adissolution rate that remain relatively stable over time.

Also provided are compositions and methods for preparing compositionsthat can minimize aeration of hydrophobic coated Ibuprofen insuspension. For example, hydrophobic coated Ibuprofen may be mixed intoa matrix solution/suspension to form a pharmaceutical suspension toaccurately dose into molds to form solid pharmaceutical compositions(e.g., article, tablet, etc.) for administering to a patient. However,the hydrophobicity of the coated Ibuprofen causes the coated Ibuprofento resist dispersing into the solution/suspension. Consequently, thiscan cause air to become entrained with the pharmaceutical suspension,also known as aeration. Entrained air, or aeration of the pharmaceuticalsuspension, can cause phase separation of the coated Ibuprofen in thepharmaceutical suspension, causing a non-homogenous pharmaceuticalsuspension. Aeration and non-homogeneous pharmaceutical suspensions canlead to poor dose weight accuracy of the pharmaceutical suspensioncomprising the hydrophobic Ibuprofen dosed into preformed blister packsand poor content uniformity in the finished product (i.e.,pharmaceutical composition).

Traditional mechanical means of anti-aeration and/or minimizing aerationhave not been found to be successful due to the high viscosity of thepharmaceutical suspension. For example, minimizing aeration may beachieved by applying vacuum to a pharmaceutical suspension, butdepending on the composition and further processing requirements thisapproach may not be suitable. In particular, applying a vacuum to thepharmaceutical suspension can cause the suspension to rise because theviscous suspension “holds onto” the entrained air. Volatile formulationcomponents may also be lost during vacuum processing. Further,traditional anti-aerating agents, such as ethanol or simethiconeemulsion are similarly ineffective at anti-aerating the suspension.

Accordingly, compositions and methods provided herein minimize theaeration of a pharmaceutical suspension comprising hydrophobic coatedIbuprofen to improve the homogeneity of the suspension and increase thedose weight accuracy. Specifically, embodiments provided can includematrix solutions/suspensions comprising chemical compounds comprisingterpene and/or terpinol. In some embodiments, a matrixsolution/suspension may comprise the terpene limonene. By introducing aterpene-comprising chemical compound such as limonene, the hydrophobiccoated Ibuprofen may more readily incorporate into the matrixsolution/suspension, minimizing the overall aeration of thepharmaceutical suspension.

Also provided herein are pharmaceutical compositions and methods forpreparing pharmaceutical compositions that are formulated to preservethe functional coating of functionally-coated Ibuprofen during themanufacture process. Functionally-coated Ibuprofen are often mixed toform a pharmaceutical suspension. A pharmaceutical suspension allows foraccurate dosing to form an administrable pharmaceutical product.Typically, shear forces required to incorporate the functionally-coatedIbuprofen into a pharmaceutical suspension can cause the functionalcoating to erode. Erosion of this coating can destroy or damage theproperties of the functional coating. Accordingly, functionally-coatedIbuprofen with an eroded coating can experience an increased dissolutionrate and decreased taste-masking properties when orally administered toa patient.

However, pharmaceutical compositions and methods for preparingpharmaceutical compositions provided herein include preserving thecoating of functionally-coated Ibuprofen in the pharmaceuticalsuspension with hydrophobic fumed silica. Specifically, the hydrophobicfumed silica can provide a protective layer surrounding and/or embeddedinto the functionally-coated Ibuprofen particle. In some embodiments,solventless processes for producing functionally-coated Ibuprofen mayproduce Ibuprofen comprising a first coating. According to someembodiments, hydrophobic fumed silica can be added during thesolventless mixing process to produce a second, protective coatingsurrounding and/or partially or fully embedded into thefunctionally-coated Ibuprofen.

Additionally, the second, protective coating may limit the interactionbetween the functionally-coated Ibuprofen and the matrixsolution/suspension such that impact of the functionally-coatedIbuprofen on the performance characteristics of the matrix is minimized.

In some embodiments, a pharmaceutical composition comprises: 65-85% w/wIbuprofen; 15-30% w/w coating material coating the Ibuprofen; and 3-15%w/w matrix surrounding the Ibuprofen. In some embodiments, thepharmaceutical composition comprises 50-400 mg Ibuprofen. In someembodiments, the coating material comprises a first coating material anda second coating material and the pharmaceutical composition comprises10-30% w/w the first coating material and 0.5-10% w/w the second coatingmaterial. In some embodiments, the first coating material comprises awax. In some embodiments, the second coating material comprises silica.In some embodiments, the pharmaceutical composition comprises 1-5% w/wanti-aerating agent. In some embodiments, the first coating materialcomprises one or more of carnauba wax, synthetic wax, or candelilla wax.In some embodiments, the matrix comprises a matrix former and astructure former. In some embodiments, the matrix former comprises oneor more of a water soluble material, a water dispersible material, apolypeptide, a polysaccharide, a polyvinyl alcohol, apolyvinylpyrrolidone, and an acacia. In some embodiments, the matrixformer comprises a polypeptide. In some embodiments, the polypeptidecomprises gelatin. In some embodiments, the structure former comprisesone or more of mannitol, dextrose, lactose, galactose, and cyclodextrinIn some embodiments, the structure former comprises mannitol. In someembodiments, the pharmaceutical composition has a disintegration time of4 seconds or less for at least one month under storage conditions of atleast 25° C. and at least 60% relative humidity. In some embodiments,the pharmaceutical composition has a disintegration time of 4 seconds orless for at least two months under storage conditions of at least 25° C.and at least 60% relative humidity. In some embodiments, thepharmaceutical composition has a disintegration time of 3 seconds orless for at least two months under storage conditions of at least 25° C.and at least 60% relative humidity. In some embodiments, thepharmaceutical composition has a disintegration time of 4 seconds orless for at least one month under storage conditions of at least 30° C.and at least 65% relative humidity. In some embodiments, thepharmaceutical composition has a disintegration time of 4 seconds orless for at least two months under storage conditions of at least 30° C.and at least 65% relative humidity. In some embodiments, thepharmaceutical composition has a disintegration time of 4 seconds orless for at least one month under storage conditions of at least 40° C.and at least 75% relative humidity. In some embodiments, thepharmaceutical composition has a disintegration time of 4 seconds orless for at least two months under storage conditions of at least 40° C.and at least 75% relative humidity. In some embodiments, thepharmaceutical composition has a disintegration time of 4 seconds orless for at least three months under storage conditions of at least 25°C. and at least 60% relative humidity. In some embodiments, thepharmaceutical composition has a disintegration time of 4 seconds orless for at least three months under storage conditions of at least 30°C. and at least 65% relative humidity. In some embodiments, thepharmaceutical composition has a disintegration time of 4 seconds orless for at least three months under storage conditions of at least 40°C. and at least 75% relative humidity. In some embodiments, thepharmaceutical composition has a disintegration time of 4 seconds orless for at least six months under storage conditions of at least 25° C.and at least 60% relative humidity. In some embodiments, thepharmaceutical composition has a disintegration time of 4 seconds orless for at least six months under storage conditions of at least 30° C.and at least 65% relative humidity. In some embodiments, thepharmaceutical composition has a disintegration time of 4 seconds orless for at least six months under storage conditions of at least 40° C.and at least 75% relative humidity. In some embodiments, thepharmaceutical composition has a dissolution test result of 10%, 5%, 3%or less after 5 minutes. In some embodiments, the matrix comprises aviscosity modifier. In some embodiments, the viscosity modifiercomprises xanthan gum. In some embodiments, the anti-aerating agentcomprises one or more of a terpene or a terpinol. In some embodiments,the anti-aerating agent comprises a liquid flavor. In some embodiments,wherein the anti-aerating agent comprises a liquid flavor comprisinglimonene. In some embodiments, the anti-aerating agent comprises one ormore of orange flavor, lemon flavor, grapefruit flavor, lime flavor,strawberry flavor, or peppermint flavor. In some embodiments, thepharmaceutical composition comprises from 3-10% w/w matrix former. Insome embodiments, the pharmaceutical composition comprises from 3-10%w/w structure former.

In some embodiments, a pharmaceutical composition can be prepared by aprocess comprising steps of: coating Ibuprofen with a first coatingmaterial to form coated Ibuprofen, wherein the first coating materialcomprises one or more deformable components; applying mechanical stressto the coated Ibuprofen to deform the one or more deformable components;coating the coated Ibuprofen with a second coating material comprisingsilica; applying mechanical stress to embed the second coating materialonto the first coating material of the coated Ibuprofen; sieving thecoated Ibuprofen to remove excess first coating material, wherein theexcess first coating material comprises first coating material not boundto the coated Ibuprofen; forming a pharmaceutical suspension comprisingthe twice coated Ibuprofen and a matrix solution or suspension; dosingthe pharmaceutical suspension into a mold; and freeze drying the dosedpharmaceutical suspension in the mold to form a pharmaceuticalcomposition. In some embodiments, sieving the coated Ibuprofen comprisespassing the coated Ibuprofen through a device comprising two or moresieves. In some embodiments, sieving the coated Ibuprofen comprisessieving the coated Ibuprofen to an average particle size of 75 μm orgreater. In some embodiments, sieving the coated Ibuprofen comprisessieving the coated Ibuprofen to an average particle size of 200 μm orless. In some embodiments, the weight of dosed pharmaceutical suspensionis within 10 percent of a target dose weight. In some embodiments, theweight of dosed pharmaceutical suspension has a consistency within 5percent of a target dose weight. In some embodiments, the weight ofdosed pharmaceutical suspension has a consistency within 2.5 percent ofa target dose weight. In some embodiments, the weight of dosedpharmaceutical suspension has a consistency within 1 percent of a targetdose weight. In some embodiments, mixing the coated Ibuprofen into amatrix solution or suspension comprises in-line mixing at 15-20° C.degrees Celsius. In some embodiments, the coated Ibuprofen experiencesless than 40% loss in particle size within the first 2 hours aftermixing into the solution matrix. In some embodiments, the coatedIbuprofen experiences less than 30% loss in particle size within thefirst 2 hours after mixing into the solution matrix. In someembodiments, the coated Ibuprofen experiences less than 20% loss inparticle size within the first 2 hours after mixing into the solutionmatrix.

In some embodiments, a method of treating a patient comprisesadministering to a patient the pharmaceutical composition of anydisclosed herein. In some embodiments, the patient is human.

In some embodiments, a method of preparing a pharmaceutical compositioncomprises: coating Ibuprofen with a first coating material to formcoated Ibuprofen, wherein the first coating material comprises one ormore deformable components; applying mechanical stress to the coatedIbuprofen to deform the one or more deformable components; coating thecoated Ibuprofen with a second coating material comprising silica;applying mechanical stress to embed the second coating material onto thefirst coating material of the coated Ibuprofen; sieving the coatedIbuprofen to remove excess first coating material, wherein the excessfirst coating material comprises first coating material not bound to thecoated Ibuprofen; forming a pharmaceutical suspension comprising thetwice coated Ibuprofen and a matrix solution or suspension; dosing thepharmaceutical suspension into a mold; and freeze drying the dosedpharmaceutical suspension in the mold to form a pharmaceuticalcomposition

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described, by way of example only, withreference to the accompanying drawings, in which:

FIG. 1A shows an API particle coated with particles of a deformablecoating material (i.e., a first coating layer) according to someembodiments;

FIG. 1B shows an API particle coated with a continuous film layer ofdeformable coating material (i.e., a first coating layer) according tosome embodiments;

FIG. 1C shows an API particle coated with a continuous film layer ofdeformable coating material (i.e., a first coating layer) with particlesof silica (i.e., a second coating layer) partially embedded and/orembedded on the surface of the first coating layer according to someembodiments;

FIG. 2 shows a scanning electron microscope (SEM) image of an un-coatedAPI particle according to some embodiments;

FIG. 3 shows an SEM image of a coated API particle, according to someembodiments;

FIGS. 4A-4J are a series of photomicrographs taken of sieved coatedIbuprofen for Examples 1-4;

FIG. 5 is a graph providing an evaluation of d10 particle size offunctionally-coated Ibuprofen comprising a second protective coating ofdifferent concentrations of silica, according to some embodiments;

FIG. 6 shows a graph providing an evaluation of d50 particle size offunctionally-coated Ibuprofen comprising a second protective coating ofdifferent concentrations of silica, according to some embodiments;

FIG. 7 shows a graph providing an evaluation of d90 particle size offunctionally-coated Ibuprofen comprising a second protective coating ofdifferent concentrations of silica, according to some embodiments;

FIG. 8 shows a graph of low volume dissolution of Ibuprofen coated withcarnauba wax with varying levels of hydrophobic fumed silica, accordingto some embodiments;

FIG. 9 shows a graph of low volume dissolution of Ibuprofen coated withSasol (synthetic) wax comprising varying levels of hydrophobic fumedsilica, according to some embodiments;

FIG. 10 shows a graph providing an evaluation of d10 particle size ofhydrophobic coated Ibuprofen with various concentrations of liquidflavor;

FIG. 11 shows a graph providing an evaluation of d50 particle size ofhydrophobic coated Ibuprofen with various concentrations of liquidflavor;

FIG. 12 shows a graph providing an evaluation of d90 particle size ofhydrophobic coated Ibuprofen with various concentrations of liquidflavor;

FIG. 13 shows a graph providing an evaluation of d10 particle size ofhydrophobic coated Ibuprofen with various concentrations of purelimonene;

FIG. 14 shows a graph providing an evaluation of d50 particle size ofhydrophobic coated Ibuprofen with various concentrations of purelimonene;

FIG. 15 shows a graph providing an evaluation of d90 particle size ofhydrophobic coated Ibuprofen with various concentrations of purelimonene; and

FIG. 16 shows a graph comparing the various particle size analyses ofhydrophobic coated Ibuprofen with strawberry and orange liquid flavors.

DETAILED DESCRIPTION

Described herein are exemplary embodiments of methods for minimizingand/or preventing the agglomeration of the coating material of coatedIbuprofen, methods for preserving the coating of coated Ibuprofen, andmethods of minimizing aeration of Ibuprofen in a pharmaceuticalsuspension. Also described are pharmaceutical compositions comprisingIbuprofen prepared by any one or more of the disclosed methods. Each ofthese methods and pharmaceutical compositions are described in detailbelow. Pharmaceutical compositions comprising Ibuprofen may be preparedusing any combination of features from the preparation methods describedbelow.

FIGS. 1A, 1B, and 1C illustrate different phases of a coated APIparticle (e.g., Ibuprofen) according to some embodiments. In someembodiments, API particles can be combined with one or more coatingmaterials to produce coated API. This coating may comprise materialsincluding a water soluble and/or water swellable material and a waterinsoluble material (described in detail below).

For example, FIG. 1A shows an API particle 102 surrounded by particlesof a coating material 104. To achieve the coated API particle of FIG.1A, the combined API (i.e., API particle 102) and one or more coatingmaterial(s) (i.e., coating material particles 104) may be exposed tomechanical and/or thermal energy to produce an ordered mixture of APIparticle 102 comprising a discrete layer of coating material particles104 layering the surface of the API particle 102. API particle 102 ofFIG. 1A is shown with a single layer of discrete particles of coatingmaterial(s). However, API particle 102 may have two or more discretelayers of coating particles. Additionally, FIG. 2 shows an SEM image ofan un-coated API particle.

FIG. 1B demonstrates API particle 102 surrounded by continuous, deformedfilm layer 104. Specifically, FIG. 1B shows that all of the coatingmaterial particles 104 may be deformable and may deform when subjectedto mechanical stress and/or elevated temperature. Thus, because all thecoating materials comprise deformable characteristics, the coatingmaterial 104 of FIG. 1B is a relatively smooth and continuous coatinglayer after exposure to mechanical and/or thermal energy. In someembodiments, API particle 102 may have two or more relatively smooth andcontinuous coating layers. “Continuous film” as used herein may be alayer surrounding an API particle formed by melting/softening orotherwise breaking down one or more deformable components of theindividual coating material particles such that they comprise a single,continuous layer surrounding the API particle. FIG. 3 also provides anSEM image showing a coated API particle according to some embodiments.

In some embodiments, one or more of the coating materials may not bedeformable but may be embedded in the deformable coating layer. Thus,the continuous film may comprise solid particles of the non-deformablematerial embedded within the deformed coating material. FIG. 1C showsthat continuous film 104 may comprise solid non-deformable particles 108of one or more non-deformable materials partially embedded and/orembedded within the deformed coating material of continuous film 104.This continuous film 104 of FIG. 1B or 1C can ensure a coating (forexample, a coating that masks the taste of the API) and a delayed APIrelease. In some embodiments, API particle 102 may have two or morecontinuous coating layers partially embedded and/or embedded withnon-deformable coating material particles. FIG. 3 also provides an SEMimage showing a functionally-coated API particle according to someembodiments.

As used herein, the terms “deformable”, “deformable components”,“deformable components of the coating material” and other related termsrefer to one or more components of the water soluble, water swellable,and/or water insoluble materials that can be broken down when subjectedto mechanical stress and/or elevated temperature.

In some embodiments, the coated API particles may comprise Ibuprofen. Insome embodiments, the coated API particles or pharmaceutical compositionmay comprise from 30.0 to 90.0% w/w Ibuprofen. In some embodiments, thecoated API particles or pharmaceutical composition may comprise from40.0 to 85.0% w/w, from 50.0 to 80.0% w/w, or from 70.0 to 80.0% w/wIbuprofen. In some embodiments, the coated API particles orpharmaceutical composition may comprise more than 40.0% w/w, more than50.0% w/w, more than 60.0% w/w, more than 65% w/w, more than 70.0% w/w,more than 75.0% w/w, more than 80.0% w/w, or more than 85.0% w/wIbuprofen. In some embodiments, the coated API particles orpharmaceutical composition may comprise less than 90.0% w/w, less than85.0% w/w, less than 80.0% w/w, less than 75.0% w/w, less than 70.0%w/w, less than 60.0% w/w, less than 50.0% w/w, or less than 40.0% w/wIbuprofen.

Coating 104 surrounding the API particle 102 may comprise materialsincluding a water soluble and/or water swellable material and a waterinsoluble material. In some embodiments, this coating may coat an APIparticle (e.g., Ibuprofen) directly, or it may coat an API particlealready comprising one or more coatings. In some embodiments, the ratioof coating material to API may be optimized to minimize excess coatingmaterial. For example, the coating material may comprise 5-85% w/w,10-50%, 15-30% of the API and coating material mixture or pharmaceuticalcomposition. In some embodiments, the coating material may comprise lessthan 85%, less than 80%, less than 75%, less than 70%, less than 65%,less than 60%, less than 55%, less than 50%, less than 45%, less than40%, less than 35%, less than 30%, less than 25%, less than 20%, lessthan 15%, or less than 10% of the API and coating material mixture orpharmaceutical composition. In some embodiments, the coating materialmay include more than 5%, more than 10%, more than 15%, more than 20%,more than 25%, more than 30%, more than 35%, more than 40%, more than45%, more than 50%, more than 55%, more than 60%, more than 65%, morethan 70%, or more than 75% of the API and coating material mixture orpharmaceutical composition. In some embodiments, the coating materialpercentage may include two or more layers of coating material.

The water swellable material of the coating material may be a particlecomprising a median particle size of about 0.5 μm to about 20 μm orabout 1 μm to about 10 μm. In some embodiments, the water swellablematerial may be approximately ten times smaller than that of theIbuprofen to enable ordered mixing and coating. The water swellablematerial can swell upon absorption of water such that a diameter of thewater swellable particle increases at least by about 120-600%. Thecoating material or pharmaceutical composition may comprise from 0 to 8%w/w or from 0.1 to 0.9% w/w water swellable materials. In someembodiments, the coating material or pharmaceutical composition maycomprise from 0.5 to 6.0% w/w, from 1.0 to 4.0% w/w, from 1.5 to 3.5%w/w, or from 2.0 to 3.0% w/w water swellable materials. In someembodiments, the coating material or pharmaceutical composition maycomprise less than 8.0% w/w, less than 6.0% w/w, less than 4.0% w/w,less than 2.0% w/w, less than 1.0% w/w, or less than 0.5% w/w waterswellable materials. In some embodiments, the coating material orpharmaceutical composition may comprise greater than 0.1% w/w, greaterthan 0.5% w/w, greater than 1.0% w/w, greater than 2.0% w/w, greaterthan 3.0 w/w %, greater than 5.0% w/w, or greater than 6.0% w/w waterswellable materials. The water swellable material of the coatingmaterial may be deformable under mechanical stress and/or elevatedtemperature (described in detail below). The water swellable materialmay be any one or more of crospovidone, croscarmellose, sodium starchglycolate, or any other suitable disintegrant used in the pharmaceuticalindustry as an additive or blend made for tableting.

The water soluble material of the coating material may also be aparticle comprising a median particle size of about 0.5 μm to about 20μm or about 1 μm to about 10 μm. In some embodiments, the water solublematerial may be approximately ten times smaller than that of theIbuprofen to enable ordered mixing and coating. The water solublematerial may have a water solubility of at least about 50 mg/ml in waterat a neutral pH and at 20° C. Further, the water soluble material canhave an intrinsic dissolution rate of about 3-60 μg/m²s. The watersoluble material of the coating material may be deformable undermechanical energy and/or thermal energy. The coating material orpharmaceutical composition may comprise from 0 to 35% w/w water solublematerials. In some embodiments, the coating material or pharmaceuticalcomposition may comprise from 0.5 to 25% w/w, from 1.0 to 15% w/w, from1.5 to 10% w/w, or from 2.0 to 3.0% w/w water soluble materials. In someembodiments, the coating material or pharmaceutical composition maycomprise less than 35% w/w, less than 30% w/w, less than 25% w/w, lessthan 20% w/w, less than 15% w/w, less than 10% w/w, less than 5.0% w/w,less than 4.5% w/w, less than 4.0% w/w, less than 3.5% w/w, less than3.0% w/w, less than 2.5% w/w, less than 2.0% w/w, less than 1.5% w/w,less than 1.0% w/w, or less than 0.5% w/w water soluble materials. Insome embodiments, the coating material or pharmaceutical composition maycomprise more than 0.1% w/w, more than 0.5% w/w, more than 1.0% w/w,more than 1.5% w/w, more than 2.0% w/w, more than 2.5% w/w, more than3.0% w/w, more than 4.0% w/w, more than 5.0% w/w, more than 8.0% w/w,more than 10% w/w, more than 15% w/w, more than 20% w/w, more than 25%w/w, or more than 30% w/w water soluble materials. The water solublematerial may be one or more of sucrose, mannitol, sorbitol,polyvinylpyrrolidone, hydroxypropylcellulose, lactose, poly-(ethyleneoxide), and any other suitable micronizable materials or polyols.

In addition to an intrinsic dissolution rate of 3-60 μg/m²s discussedabove, processes provided can permit the use of water soluble and/orwater swellable materials having a higher intrinsic dissolution rate ofabout 60-300 μg/m²s as well. However, Ibuprofen with coating materialshaving a higher intrinsic dissolution rate should be dry coated withhydrophobic silica. Dry coating Ibuprofen wherein the coating compriseswater soluble and/or water swellable materials having higher intrinsicdissolution rates can increase the disintegration time of the ibuprofen,such that they are incapable of masking the Ibuprofen's tasteeffectively. Accordingly, dry coating the Ibuprofen with silica as asecond coating material to slow the dissolution rate can improve thein-vivo taste-masking performance of the coating. The coated Ibuprofenmay comprise from 0.5 to 35% w/w silica. In some embodiments, the coatedIbuprofen or pharmaceutical composition can comprise from 0.5 to 20%w/w, from 0.5 to 10% w/w, or from 0.5 to 5% w/w hydrophobic fumedsilica. In some embodiments, the coated Ibuprofen or pharmaceuticalcomposition can comprise more than 0.5% w/w, more than 1.0% w/w, morethan 1.5% w/w, more than 2.0% w/w, more than 2.5% w/w, more than 3.0%w/w, more than 4.0% w/w, more than 5.0% w/w, more than 10% w/w, morethan 15% w/w, more than 20% w/w, more than 25% w/w, or more than 30% w/whydrophobic fumed silica. In some embodiments, the coated Ibuprofen orpharmaceutical composition can comprise less than 35% w/w, less than 25%w/w, less than 15% w/w, less than 10% w/w, less than 5.0% w/w, less than4.0% w/w, less than 3.5% w/w, less than 3.0% w/w, less than 2.5% w/w,less than 2.0% w/w, less than 1.5% w/w, or less than 1.0% w/whydrophobic fumed silica. Examples of silica that may be used include,but are not limited to, Aerosil R972 silica (Degussa), CAB-O-SIL EH-5silica (Cabot), OX-50 silica (Degussa), COSM055 (Catalyst & ChemicalInd. Co. Ltd (Japan)), P-500 hydrophilic silica (Catalyst & ChemicalInd. Co. Ltd (Japan)), and TS5 silica (Cabot). Further, suitable devicesthat may be used to dry coat with silica include, but are not limitedto, Comil (U3 Quadro Comil of Quadro Pennsylvania, U.S.), LabRAM(Resodyne Minnesota, U.S.), Magnetically Assisted Impact Coater (MAIC,Aveka Minnesota, U.S.), and Fluid Energy Mill (FEM, QualificationMicronizer of Sturtevant Massachusetts U.S.).

A pharmaceutical composition may be prepared by dosing thepharmaceutical suspension into preformed blister packs. In someembodiments, a freeze-dried orally disintegrating tablet may be preparedby dosing the suspension into blister packs. In some embodiments, dosingpumps pump by volume, but the process is controlled by weight. Thus, toensure content uniformity from one dosage form to the next, the dosingprocess may be controlled such that the volume-to-weight percentage ofdosed suspension is consistent. For example, a volume-to-weightpercentage may be consistent within 10 percent, within 8 percent, within6 percent, within 5 percent, within 4 percent, within 3 percent, within2 percent, within 1.5 percent, within 1 percent, within 0.5 percent, orwithin 0.25 percent. In some embodiments, the weight of the dosedpharmaceutical suspension is within 10 percent, within 8 percent, within6 percent, within 5 percent, within 4 percent, within 2.5 percent,within 2 percent, within 1.5 percent, within 1 percent, within 0.5percent, or within 0.25 percent of a target weight. Additionally, theviscosity of the pharmaceutical suspension should be kept low enough forease of dosing. As described above, a high viscosity of thepharmaceutical suspension can case pump seizures during dosing.

The water insoluble material of the coating materials may also be aparticle comprising an average particle size less than that of theIbuprofen. For example, the water insoluble material(s) may comprise anaverage particle size from about 1-20 μm, about 1-12 μm, about 2-10 μm,about 5-12 μm, or about 5-6 μm. In some embodiments, the water insolublematerial may be approximately ten times smaller than that of theIbuprofen to enable ordered mixing and coating. The water insolublematerial of the coating material may be deformable under mechanicalstress and/or elevated temperature. The coating material orpharmaceutical composition may comprise from 5 to 70% w/w, from 10 to60% w/w, from 10 to 50% w/w, from 10 to 40% w/w, from 10 to 35% w/w, orfrom 15 to 30% w/w water insoluble materials. In some embodiments, thecoating material or pharmaceutical composition may comprise more than 5%w/w, more than 10% w/w, more than 15% w/w, more than 20% w/w, more than25% w/w, more than 30% w/w, more than 35% w/w, or more than 40% w/wwater insoluble materials. In some embodiments, the coating material orpharmaceutical composition may comprise less than 70% w/w, less than 60%w/w, less than 50% w/w, less than 45% w/w, less than 40% w/w, less than35% w/w, or less than 30% w/w water insoluble materials. Examples ofsuitable water insoluble materials include, but are not limited toethylcellulose, polyethylene, polypropylene, polytetrafluoroethylene,carnauba wax, candelilla wax, castor wax, polyamide wax and/or syntheticwax.

In some embodiments, mechanical and/or thermal energy may be used todeform the one or more water insoluble materials, water swellablematerials, and/or water insoluble materials. For example, mechanicalstress can be applied to the functionally-coated Ibuprofen using aPharmaRAM II acoustic mixer, a RAM 5 Pharma mixer, or a RAM 55 Pharmamixer (Resodyn Mixers). The coated Ibuprofen may be exposed to up to 100times the force of gravity (100G acceleration) during this acousticmixing process. These high forces cause particle-particle collisionsthat generate energy in the form of heat, which may be used to deformthe one or more water insoluble materials, water swellable materials,and/or water insoluble materials onto the API.

However, the coating process described above can also generate “loose”,or “free” coating material particles. FIG. 2 is an SEM image of anuncoated API particle. FIG. 3 is an SEM image of coated API particle312. “Loose” or “free” coating material particles 314 are not bound tocoated API particle 312.

Once sieved, the coated Ibuprofen can be mixed into a matrixsolution/suspension to form a pharmaceutical suspension (e.g., coatedIbuprofen plus matrix solution/suspension) and dosed by weight intopockets of preformed blister packs to form aliquots of pharmaceuticalsuspension. Once dosed, the blister packs with aliquots pharmaceuticalsuspension are frozen under sub-zero conditions. The frozen aliquots ofdosed pharmaceutical suspension is held frozen until it is ready forfreeze drying during which the solvent of the pharmaceutical suspensionis removed to form the pharmaceutical composition.

The matrix solution/suspension may include a matrix former, a structureformer, and a solvent. For example, the matrix former may include anywater soluble or water dispersable material that is pharmacologicallyacceptable or inert to the functionally-coated Ibuprofen. In someembodiments, the matrix former may be a polypeptide such as gelatin. Thegelatin may be at least partially hydrolyzed (by heating in water).Other suitable matrix former materials include, but are not limited to,polysaccharides such as hydrolyzed dextran, dextrin, and alginates,polyvinyl alcohol, polyvinylpyrrolidone, and/or acacia. In someembodiments, the amount of matrix in a pharmaceutical composition (e.g.,an orally disintegrating tablet) may be 1-30% w/w. In some embodiments,the amount of matrix may be less than 30% w/w, less than 25% w/w, lessthan 20% w/w, less than 15% w/w, less than 10% w/w, less than 5% w/w, orless than 3% w/w. In some embodiments, the amount of matrix may be morethan 1% w/w, more than 3% w/w, more than 5% w/w, more than 10% w/w, morethan 15% w/w, more than 20% w/w, or more than 25% w/w.

In some embodiments, the amount of matrix former in a matrixsolution/suspension or pharmaceutical suspension can be from about 0.1to 10% w/w. In some embodiments, the amount of matrix former in thematrix solution/suspension or pharmaceutical suspension may include from1.0 to 8.0% w/w or from 2.0 to 5.0% w/w. In some embodiments, the amountof matrix former in the matrix solution/suspension or pharmaceuticalsuspension may include more than 0.1% w/w, more than 0.5% w/w, more than1.0% w/w, more than 2.0% w/w, more than 3.0% w/w, more than 4.0% w/w,more than 4.5% w/w, more than 5.0% w/w, or more than 8.0% w/w. In someembodiments, the amount of matrix former in the matrixsolution/suspension or pharmaceutical suspension may include less than10% w/w, less than 8.0% w/w, less than 6.0% w/w, less than 5.0% w/w,less than 4.0% w/w, less than 3.0% w/w, less than 2.5% w/w, less than2.0% w/w, less than 1.5% w/w, or less than 1.0% w/w. In someembodiments, the amount of matrix former in a pharmaceutical compositioncan be about 3-15% w/w, about 4-10% w/w, or about 4-7% w/w. In someembodiments, the amount of matrix former in the pharmaceuticalcomposition may include more than 0.1% w/w, more than 0.5% w/w, morethan 1.0% w/w, more than 2.0% w/w, more than 3.0% w/w, more than 4.0%w/w, more than 5.0% w/w, more than 6.0% w/w, more than 7.0% w/w, morethan 8.0% w/w, more than 9.0% w/w, more than 10.0% w/w, more than 11.0%w/w, more than 12.0% w/w, more than 13.0% w/w, or more than 14.0% w/w.In some embodiments, the amount of matrix former in the pharmaceuticalcomposition may include less than 15% w/w, less than 14.0% w/w, lessthan 13.0% w/w, less than 12.0% w/w, less than 10.0% w/w, less than 9.0%w/w, less than 8% w/w, less than 7% w/w, less than 6% w/w, less than 5%w/w, or less than 4.0% w/w.

A structure former, or bulking agent, of the matrix may include a sugar.For example, suitable structure formers include, but are not limited to,mannitol, dextrose, lactose, galactose, glycine, cyclodextrin, orcombinations thereof. The structure former can be used in freeze dryingas a bulking agent as it crystallizes to provide structural robustnessto the freeze-dried dosage form. In some embodiments, the amount ofstructure former in the matrix solution/suspension can be from about 0.1to 10% w/w. In some embodiments, the amount of structure former in thematrix solution/suspension or pharmaceutical suspension may include from1.0 to 8.0% w/w or from 1.5 to 5.0% w/w. In some embodiments, the amountof structure former in the matrix solution/suspension or pharmaceuticalsuspension may include more than 0.1% w/w, more than 0.5% w/w, more than1.0% w/w, more than 2.0% w/w, more than 3.0% w/w, more than 4.0% w/w,more than 4.0% w/w, more than 5.0% w/w, or more than 8.0% w/w. In someembodiments, the amount of structure former in the matrixsolution/suspension or pharmaceutical suspension may include less than10% w/w, less than 8.0% w/w, less than 6.0% w/w, less than 5.0% w/w,less than 4.0% w/w, less than 3.0% w/w, less than 2.5% w/w, less than2.0% w/w, less than 1.5% w/w, or less than 1.0% w/w. In someembodiments, the amount of structure former in a pharmaceuticalcomposition can be about 3-15% w/w, about 4-10% w/w, or about 4-7% w/w.In some embodiments, the amount of structure former in thepharmaceutical composition may include more than 0.1% w/w, more than0.5% w/w, more than 1.0% w/w, more than 2.0% w/w, more than 3.0% w/w,more than 4.0% w/w, more than 5.0% w/w, more than 6.0% w/w, more than7.0% w/w, more than 8.0% w/w, more than 9.0% w/w, more than 10.0% w/w,more than 11.0% w/w, more than 12.0% w/w, more than 13.0% w/w, or morethan 14.0% w/w. In some embodiments, the amount of structure former inthe pharmaceutical composition may include less than 15% w/w, less than14.0% w/w, less than 13.0% w/w, less than 12.0% w/w, less than 10.0%w/w, less than 9.0% w/w, less than 8% w/w, less than 7% w/w, less than6% w/w, less than 5% w/w, or less than 4.0% w/w.

In some embodiments, a matrix solution/suspension and pharmaceuticalsuspension may include a viscosity modifier. For example, a viscositymodifier according to embodiments provided herein may include vegetablegums such as xanthan gum, alginin, guar gum, or locust bean gum,proteins such as collagen or gelatin, sugars such as agar, carboxymethylcellulose, pectin, or carrageenan, starches such as arrowroot,cornstarch, katakuri starch, potato starch, sago, or tapioca, and/orother suitable viscosity modifiers. In some embodiments, the amount ofviscosity modifier in the matrix solution/suspension, pharmaceuticalsuspension, or the pharmaceutical composition may be from 0 to 0.2% w/wor from 0.01 to 0.1% w/w. In some embodiments, the amount of viscositymodifier in the matrix solution/suspension, pharmaceutical suspension,or the pharmaceutical composition may be greater than 0.01% w/w, greaterthan 0.03% w/w, greater than 0.05% w/w, greater than 0.07% w/w, greaterthan 0.1% w/w, greater than 0.12% w/w, greater than 0.15% w/w, orgreater than 0.17% w/w. In some embodiment, the amount of viscositymodifier in the matrix solution/suspension, pharmaceutical suspension,or the pharmaceutical composition may be less than 0.2% w/w, less than0.18% w/w, less than 0.15% w/w, less than 0.12% w/w, less than 0.1% w/w,less than 0.08% w/w, less than 0.06% w/w, or less than 0.03% w/w.

The solvent of the matrix solution/suspension and pharmaceuticalsuspension may be water, but the suspension solution may include acosolvent as well. In some embodiments, the solvent can be ethanol,alcohol, isopropanol, other lower alkanols, water (e.g., purifiedwater), or combinations thereof. For example, a suitable solvent and/orcosolvent may be an alcohol, such as tert-butyl alcohol. In someembodiments, the balance remaining of the pharmaceutical suspension isthe solvent (i.e., Q.S. 100%).

The matrix solution/suspension and pharmaceutical suspension may alsocontain additional pharmaceutically acceptable agents or excipients.Such additional pharmaceutically acceptable agents or excipientsinclude, without limitation, sugars, inorganic salts, such as sodiumchloride and aluminum silicates, modified starches, preservatives,antioxidants, viscosity enhancers, coloring agents, flavoring agents, pHmodifiers, sweeteners, taste-masking agents, and combinations thereof.Suitable coloring agents can include red, black and yellow iron oxidesand FD & C dyes such as FD & C Blue No. 2 and FD & C Red No. 40, andcombinations thereof. Suitable flavoring agents can include mint,raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherryand grape flavors and combinations of these. Suitable pH modifiers caninclude citric acid, tartaric acid, phosphoric acid, hydrochloric acid,maleic acid, sodium hydroxide (e.g., 3% w/w sodium hydroxide solution),and combinations thereof. Suitable sweeteners can include aspartame,acesulfame K and thaumatin, and combinations thereof. Suitabletaste-masking agents can include sodium bicarbonate, ion-exchangeresins, cyclodextrin inclusion compounds, adsorbates ormicroencapsulated actives, and combinations thereof. One of ordinaryskill in the art can readily determine suitable amounts of these variousadditional excipients if desired.

Minimizing and/or Preventing the Agglomeration of the Coating Materialof Coated Ibuprofen

Described below are methods for preparing pharmaceutical compositionscomprising Ibuprofen that minimize the amount of excess coating materialand/or the amount of agglomeration of excess coating material onstorage.

Methods according to some embodiments include removing excess coatingmaterial particles to minimize and/or to prevent agglomeration ofcoating material in a pharmaceutical product. In some embodiments,methods may include sieving the raw Ibuprofen and/or the coatedIbuprofen. Specifically, methods provided may include sieving theIbuprofen and/or the coated Ibuprofen to remove any undesired particles,such as excess coating material particles. Sieving processes accordingto embodiments disclosed may help prevent and/or minimize the potentialof coating material agglomeration that can adversely affect adisintegration time and/or a dissolution rate of the final product.Methods may also include optimizing the coating and/or dosing ratios ofthe process.

Methods for minimizing and or preventing agglomeration of coatingmaterial particles according to embodiments described herein may beapplied to dry, solventless mixing processes for coating Ibuprofen.Accordingly, methods provided are described below in context of one ormore dry, solventless mixing processes for coating Ibuprofen. However,other variations of coating/encapsulating processes may be used as well.For example, sugar coating, film coating, other variations ofmicroencapsulation, compression coating, other variations of drycoating, melting coating, dip coating, rotary die coating, electrostaticcoating, and/or other suitable types of coating may be used.

Generally, a solventless mixing process for coating Ibuprofen includesmixing coating materials with Ibuprofen to produce coated Ibuprofen. Thecoated Ibuprofen are then stressed mechanically and/or thermally todeform the deformable coating material, creating a continuous filmsurrounding the Ibuprofen. The coated Ibuprofen are then mixed with amatrix solution/suspension to form the pharmaceutical suspension. Thepharmaceutical suspension comprising the coated Ibuprofen can be dosedinto preformed molds, such as blister packs, and further treated toproduce a dispensable pharmaceutical composition (e.g., a lyophilizate,a wafer, a tablet, etc.).

However, when the final product (i.e., pharmaceutical composition) isstored, any excess coating material particles not bound to coatedIbuprofen can agglomerate. The amount and/or severity of agglomerationmay increase over time. Agglomeration of excess coating material canincrease the disintegration times and/or decrease the dissolution rateof the pharmaceutical product and adversely affect any functionalproperties of the coating material. An increased disintegration time mayalso cause unacceptable dispersion and mouthfeel characteristics invivo.

Accordingly, it has been discovered that by sieving the coatedIbuprofen, excess coating material can be removed, thus minimizing theamount of agglomeration of excess coating material upon storage.Further, some embodiments include optimizing the coating ratio (amountof coating materials to the amount of uncoated Ibuprofen) and optimizingthe dosing ratio (amount of coated Ibuprofen to the aqueous solutionmatrix comprising all the other inactive ingredients) can also minimizethe agglomeration of excess coating material particles.

Embodiments provided herein can be applied to coated Ibuprofen producedusing dry, solventless processes. Some mixing processes according toembodiments described herein include coating Ibuprofen with ataste-masking coating. Such coatings can control the disintegration timeand/or the dissolution rate of an orodispersible pharmaceuticalcomposition such that the release of the Ibuprofen upon oraladministration is delayed or significantly reduced during the first fewminutes when it is in the mouth, yet a satisfactory amount of theIbuprofen is released within 30 minutes from oral administration postswallowing. (For example, a satisfactory amount of Ibuprofen may be 90%of the Ibuprofen amount which would be released without the coating).U.S. Pat. No. 9,107,851 (the '851 patent) is directed to an example dry,solventless process for coating pharmaceutical ingredients, the entiretyof which is incorporated herein.

However, other variations of coating/encapsulating processes may be usedas well. For example, sugar coating, film coating, other variations ofmicroencapsulation, compression coating, other variations of drycoating, melting coating, dip coating, rotary die coating, electrostaticcoating, and/or other suitable types of coating may be used.

Additionally, specific data as provided herein is related todisintegration times. However, disintegration time is inversely relatedto dissolution rates. Thus, the data inherently provides information ondissolution rates as well. Disintegration time may be measured accordingto methods set forth by the United States Pharmacopeia (Disintegration701). In some embodiments, the disintegration time may be from 2-30seconds or 5-20 seconds. In some embodiments, the disintegration timemay be less than 30 seconds, less than 25 seconds, less than 20 seconds,less than 15 seconds, less than 10 seconds, or less than 5 seconds. Insome embodiments, the disintegration time may be greater than 2 seconds,greater than 5 seconds, greater than 10 seconds, greater than 15seconds, greater than 20 seconds, or greater than 25 seconds. Similarly,dissolution rate may also be tested according to methods set forth bythe United States Pharmacopeia (Dissolution 711).

In some embodiments, raw Ibuprofen may be sieved prior to the coatingprocess to achieve a narrower particle size range. For example, the rawIbuprofen may be sieved to remove oversized particles and/or to removeundersized particles. In some embodiments, more than one mesh can beused to remove certain particles. For example, a sieving device maycomprise a series of two or more meshes to remove particles of a certainsize according to the size of the mesh(s). The sieve can incorporate avacuum transfer system to transport the particles through the series ofmeshes of the device. Additionally, ultrasonic probes may beincorporated into the sieving device to improve material flow andminimize blinding of the mesh during processing.

In some embodiments, the raw Ibuprofen can be sieved using a mesh sizefrom 30 μm to 500 μm, from 50 μm to 450 μm, from 100 μm to 400 μm, from150 μm to 350 μm, or from 200 μm to 300 μm. In some embodiments, the rawIbuprofen can be sieved using a mesh size less than 500 μm, less than450 μm, less than 400 μm, less than 350 μm, less than 300 μm, less than250 μm, less than 200 μm, less than 150, or less than 100 μm. In someembodiments, the raw Ibuprofen can be sieved using a mesh size greaterthan 30 μm, greater than 50 μm, greater than 100 μm, greater than 150μm, greater than 200 μm, greater than 250 μm, greater than 300 μm,greater than 350 μm, or greater than 400 μm.

Once the Ibuprofen have been coated by the coating material to producecoated Ibuprofen, the coated Ibuprofen may be sieved to remove excesscoating material and residual fine Ibuprofen, either uncoated, partiallycoated or coated. Excess coating material may include any coatingmaterial particles not bound to a coated Ibuprofen. Upon storage of thefinal pharmaceutical product, any excess coating material canagglomerate. For example, fusion may occur between excess coatingparticles and coating particles that are already bound to an Ibuprofen,preventing ingress of media that would otherwise aid in disintegrationof the unit or tablet or dissolution of the coated Ibuprofen.Accordingly, agglomeration of excess coating material can causeincreased disintegration times and/or decreased dissolution rates uponadministration.

However, it has been determined that methods of sieving excess coatingmaterial from the coated Ibuprofen can minimize agglomeration of thecoating material and maintain the initial disintegration time and/ordissolution rate of the final product. The sieving process can be eitherbatch or continuous. Additionally, this sieving process may be performedin addition to or in lieu of the sieving process performed on rawIbuprofen, described above. In some embodiments, the sieving processparameters may be different between the uncoated, raw Ibuprofen and thecoated Ibuprofen.

In some embodiments, coated Ibuprofen may be sieved to remove coatingmaterial particles having an average particle size less than a desiredaverage coated Ibuprofen particle size. In some embodiments, more thanone mesh can be used to remove certain particles. For example, a sievingdevice may comprise a series of two or more meshes to remove particlesof a certain size according to the size of the mesh(s). The sieve canincorporate a vacuum transfer system to deliver the particles to theseries of meshes of the device. Additionally, ultrasonic probes may beincorporated into the sieving device to improve material flow andminimize blinding of the mesh during processing. A flow aid (e.g.,silica) may be included to promote movement through the sieve. Forexample, the coating material used to coat the Ibuprofen may comprise aflow aid. Conversely, raw Ibuprofen may not be cohesive and not requirethe assistance of a flow aid during sieving. The sieving process may bea batch process or a continuous process.

In some embodiments, the raw Ibuprofen can be sieved using a mesh sizefrom 30 μm to 500 μm, from 50 μm to 450 μm, from 100 μm to 400 μm, from150 μm to 350 μm, or from 200 μm to 300 μm. In some embodiments, the rawIbuprofen can be sieved using a mesh size less than 500 μm, less than450 μm, less than 400 μm, less than 350 μm, less than 300 μm, less than250 μm, less than 200 μm, less than 150, or less than 100 μm. In someembodiments, the raw Ibuprofen can be sieved using a mesh size greaterthan 30 μm, greater than 50 μm, greater than 100 μm, greater than 150μm, greater than 200 μm, greater than 250 μm, greater than 300 μm,greater than 350 μm, or greater than 400 μm.

The coating ratio (i.e., the amount of coating materials to the amountof uncoated Ibuprofen) may be optimized to minimize and/or prevent theagglomeration of the excess coating materials. For example, in someembodiments, the coating ratio can ranges from 5-85% or 10-50% w/wcoating materials to 15-95% or 50-90% w/w uncoated Ibuprofen. In someembodiments, the amount of coating materials may be less than 80% w/w,less than 70% w/w, less than 60% w/w, less than 50% w/w, less than 40%w/w, less than 30% w/w, less than 20% w/w, or less than 10% w/w. In someembodiments, the amount of coating materials may be more than 5% w/w,more than 10% w/w, more than 20% w/w, more than 30% w/w, more than 40%w/w, more than 50% w/w, more than 60% w/w, or more than 70% w/w. In someembodiments, the amount of uncoated Ibuprofen may be less than 95% w/w,less than 85% w/w, less than 75% w/w, less than 65% w/w, less than 55%w/w, less than 45% w/w, less than 35% w/w, or less than 25% w/w. In someembodiments, the amount of uncoated API may be more than 20% w/w, morethan 30% w/w, more than 40% w/w, more than 50% w/w, more than 60% w/w,more than 70% w/w, more than 80% w/w, or more than 90% w/w.

The dosing ratio (i.e., the amount of coated Ibuprofen to the amount ofmatrix solution/suspension comprising all the inactive ingredients) maybe optimized to minimize and/or prevent the agglomeration of the excesscoating materials. For example, in some embodiments, the dosing ratiocan range from 5-60% w/w coated Ibuprofen to 40-95% w/w matrixsolution/suspension. In some embodiments, the dosing ratio may includeless than 60% w/w, less than 50% w/w, less than 40% w/w, less than 30%w/w, less than 20% w/w, or less than 10% w/w coated Ibuprofen. In someembodiments, the dosing ratio may include more than 5% w/w, more than10% w/w, more than 20% w/w, more than 30% w/w, more than 40% w/w, ormore than 50% w/w coated Ibuprofen. In some embodiments, the dosingratio may include less than 95% w/w, less than 90% w/w, less than 80%w/w, less than 70% w/w, less than 60% w/w, or less than 50% w/w matrixsolution/suspension. In some embodiments, the dosing ration may includemore than 40% w/w, more than 50% w/w, more than 60% w/w, more than 70%w/w, more than 80% w/w, or more than 90% w/w matrix solution/suspension.

Preserving Functionally-Coated Ibuprofen Produced by a Dry, SolventlessMixing Process and Mixed in a Suspension

Pharmaceutical compositions and methods for preparing pharmaceuticalcompositions provided herein may include adding hydrophobic fumed silicaduring the coating process to provide a protective layer surroundingand/or partially or fully embedded into a functional (or “firstcoating”) of the functionally-coated Ibuprofen. The addition of thishydrophobic fumed silica layer (or “second layer”) can provide aprotective layer to a first coating layer of functionally-coatedIbuprofen and can minimize erosion of the first coating layer from shearforces necessary to mix the functionally-coated Ibuprofen intopharmaceutical suspension.

Generally, a solventless mixing process for coating Ibuprofen includesmixing coating materials with Ibuprofen to produce functionally-coatedIbuprofen. The functionally-coated Ibuprofen are then stressedmechanically and/or thermally to deform the deformable coating material,creating a continuous film surrounding the Ibuprofen. Thefunctionally-coated Ibuprofen are then mixed with a matrix solution orsuspension to form the pharmaceutical suspension. The pharmaceuticalsuspension comprising the functionally-coated Ibuprofen can be dosedinto preformed molds, such as blister packs, and further treated toproduce a dispensable pharmaceutical composition (e.g., a lyophilizate,a wafer, a tablet, etc.). In some embodiments, the dispensablepharmaceutical composition may be an orodispersible product. Ideally, aminimal amount, if any, of the Ibuprofen of the final dispensablepharmaceutical composition dissolves within the first few minutes oforal administration. This delay, or substantial reduction of Ibuprofenrelease, allows for the taste of the Ibuprofen to be masked when theorodispersible product is in a patient's mouth. Instead, the Ibuprofencan release once the pharmaceutical composition has passed to thegastrointestinal tract.

However, when the functionally-coated Ibuprofen are mixed into a matrixsolution/suspension, the shear forces required to mix the particles intothe matrix solution/suspension can erode the functional coating of theIbuprofen. Erosion of the coating can destroy or damage the propertiesof the functional coating. For example, erosion of the functionalcoating can destroy or damage any taste-masking properties of thefunctional coating and allow the Ibuprofen to undergo dissolution in theoral cavity.

Accordingly, it has been discovered that hydrophobic fumed silica, aswell as being used as a flow aid for the functionally-coated Ibuprofento aid downstream processing, may also be used to provide a hydrophobicbarrier layer surrounding and/or partially or fully embedded into thefunctionally-coated Ibuprofen. Specifically, the hydrophobic barrierlayer formed by the hydrophobic fumed silica can protect one or moreunderlying coatings of the functionally-coated Ibuprofen duringpreparation of the pharmaceutical suspension and other downstreamprocessing of the functionally-coated Ibuprofen. Thus, Ibuprofenaccording to some embodiments described herein may have a first,functional coating and a second, protective coating

However, some pharmaceutical compositions and methods of preparingpharmaceutical compositions provided herein may include more than afirst coating and a second coating. For example, some pharmaceuticalcompositions and methods of preparing the same may include three, four,five, six, or more coatings. Thus, the terms “first coating” and “secondcoating” as used herein should not be construed narrowly. As usedherein, the term “first coating” refers to a functional coating ofIbuprofen, and “second coating” refers to a protective coatingcomprising silica. In some embodiments, functionally-coated Ibuprofenmay have one or more coating layers between a “first coating” and a“second coating”. In some embodiments, functionally-coated Ibuprofen mayhave one or more coating layers between the Ibuprofen and the “firstcoating”. In some embodiments, a functionally-coated Ibuprofen may haveone or more coating layers on top of a “second coating”.

Once the functionally-coated Ibuprofen are prepared, they can be mixedinto the matrix/suspension solution to form a pharmaceutical suspensionfor dosing. Mixing functionally-coated Ibuprofen into a matrixsolution/suspension can erode the functional coating of thefunctionally-coated Ibuprofen. In some embodiments, to minimize thiserosion, hydrophobic fumed silica can be used to form a second coatinglayer surrounding and/or partially embedded and/or embedded into thefunctionally-coated Ibuprofen.

However, coating functionally-coated Ibuprofen (i.e., Ibuprofencomprising at least a first coating, as described above) that will laterbe mixed into a matrix solution/suspension with hydrophobic fumed silicais not naturally intuitive. As described above, to create anorodispersible pharmaceutical composition according to embodimentsdescribed herein, the functionally-coated Ibuprofen are mixed into amatrix solution/suspension comprising a matrix former, a structureformer, and a solvent (often water) to form a pharmaceutical suspension.However, a hydrophobic material is naturally resistant to mixing into amatrix solution/suspension. Accordingly, one might assume thathydrophobic fumed silica would increase the interfacial tension betweenthe functionally-coated Ibuprofen and the matrix solution/suspension,increasing the difficulty of incorporating the functionally-coatedIbuprofen into the matrix solution/suspension and potentially causingphase separation of the pharmaceutical suspension.

Interestingly, it has been determined that hydrophobic fumed silica canbe used to coat functionally-coated Ibuprofen comprising to preserve thefirst, functional coating without substantially interfering with theincorporation of the functionally-coated Ibuprofen into the matrixsolution/suspension. As described above, a hydrophobic material in amatrix solution/suspension, such as the functionally-coated Ibuprofencovered with the hydrophobic fumed silica in the matrixsolution/suspension described above, characteristically exhibits arelatively high surface tension between the hydrophobic material and thematrix solution/suspension. Accordingly, the surface tension between thehydrophobic functionally-coated Ibuprofen and the matrixsolution/suspension is likely relatively high as well.

However, as discussed below, the matrix solution/suspension may comprisea matrix former such as gelatin. Some matrix formers, including gelatin,are mild surfactants, meaning that they can lower the surface tensionbetween two materials. Accordingly, it is believed that matrix formersexhibiting surfactant-like behaviors can reduce the surface tensionbetween the functionally-coated Ibuprofen and the matrixsolution/suspension, which in turn allows for incorporation of thefunctionally-coated Ibuprofen into the matrix solution/suspension, whileat the same time maintaining the protective properties of thehydrophobic fumed silica coating layer with respect to the first,functional coating of the functionally-coated Ibuprofen. This secondcoating layer comprising hydrophobic fumed silica can provide ahydrophobic barrier to the underlying first coating of thefunctionally-coated Ibuprofen, to protect the underlying first coatingfrom the shear forces required to mix the functionally-coated Ibuprofeninto a pharmaceutical suspension. By coating the functionally-coatedIbuprofen with a hydrophobic barrier comprising hydrophobic fumedsilica, the underlying (first) coating may be protected from erosion.Further, using hydrophobic fumed silica according to described methodscan prevent the matrix solution/suspension from penetrating through thecoating to the Ibuprofen.

Under normal processing conditions, without a hydrophobic fumed silicacoating layer, the coating of the functionally-coated Ibuprofen canerode over time under the shear forces required to mix thefunctionally-coated Ibuprofen into the matrix solution/suspension.However, there can be a “processing window” of two or more hours fromthe time the functionally-coated Ibuprofen are first mixed into thematrix solution/suspension wherein the coating can remain intact and itsfunctionality can remain uncompromised. The exact time of this“processing window” varies and can depend upon the composition of thevarious components of the functionally-coated Ibuprofen, the compositionof the matrix solution/suspension, the amount of material used toprepare the coating of the functionally-coated Ibuprofen, and/or thephysicochemical properties of the Ibuprofen. However, withfunctionally-coated Ibuprofen having a second coating comprising fumedsilica, this “processing window” can be extended.

In some embodiments, the pharmaceutical composition or the coatedIbuprofen can comprise from 0.5 to 35% w/w hydrophobic fumed silica. Insome embodiments, the pharmaceutical composition or the coated Ibuprofencan comprise from 0.5 to 20% w/w, from 0.5 to 10% w/w, or from 0.5 to 5%w/w hydrophobic fumed silica. In some embodiments, the pharmaceuticalcomposition or the coated Ibuprofen can comprise more than 0.5% w/w,more than 1.0% w/w, more than 1.5% w/w, more than 2.0% w/w, more than2.5% w/w, more than 3.0% w/w, more than 4.0% w/w, more than 5.0% w/w,more than 10% w/w, more than 15% w/w, more than 20% w/w, more than 25%w/w, or more than 30% w/w hydrophobic fumed silica. In some embodiments,the pharmaceutical composition or the coated Ibuprofen can comprise lessthan 35% w/w, less than 25% w/w, less than 15% w/w, less than 10% w/w,less than 5.0% w/w, less than 4.0% w/w, less than 3.5% w/w, less than3.0% w/w, less than 2.5% w/w, less than 2.0% w/w, less than 1.5% w/w, orless than 1.0% w/w hydrophobic fumed silica. The hydrophobic fumedsilica may be any of Aerosil R972 silica (Degussa), CAB-O-SIL EH-5silica (Cabot), OX-50 silica (Degussa), COSM055 (Catalyst & ChemicalInd. Co. Ltd (Japan)), TS5 silica (Cabot), and/or other suitable typesof silica.

The effectiveness of the hydrophobic fumed silica-comprising protectivelayer can be determined by measuring the particle size of thefunctionally-coated Ibuprofen in the pharmaceutical suspension overtime. If the hydrophobic fumed silica is effective at preserving thecoating, the particle size of the functionally-coated Ibuprofen canremain constant or decrease very little over time. If ineffective, theparticle size of the functionally-coated Ibuprofen can decrease moresubstantially over time. The particle size of the functionally-coatedparticles can be measured using laser diffraction, a particle analyzersuch as a Malvern Mastersizer, or any other suitable means for analyzingfine particles.

The effectiveness of the hydrophobic fumed silica-comprising protectivelayer can also be determined by conducting dissolution testing on thefunctionally-coated Ibuprofen. If the hydrophobic fumed silica iseffective at preserving the coating, the release amount (e.g., percentof release) of the functionally-coated Ibuprofen over time will beslower in dissolution testing. If ineffective, the release amount of thefunctionally-coated Ibuprofen over time will be greater. The releaseamount of the functionally-coated particles can be measured usingdissolution testing, a spectrophotometric analyzer such as a PionMicroDISS Profiler, or any other suitable means for conductingdissolution testing.

Minimizing the Aeration of Suspensions Comprising Ibuprofen

Embodiments provided herein may include adding a chemical compoundcomprising terpene and/or terpinol to the matrix solution/suspension.Specifically, embodiments of the pharmaceutical suspensions providedherein may include liquid flavors comprising terpene and/or terpinols.In some embodiments, the liquid flavor(s) may include the terpenelimonene. Particular chemical compounds, and specifically the additionof liquid flavors comprising limonene, can minimize the aeration of thesuspension, increase the homogeneity of the suspension, and improve thedose weight accuracy when the suspension is injected into molds. As usedherein, “dose weight accuracy” and related terms refer to the ability toaccurately dispense a pharmaceutical suspension into a pre-formed mold.The dose weight accuracy of the dosed pharmaceutical suspension maydepend on a number of variables, including, but not limited to,homogeneity, viscosity, chemical components, dosing instrument, etc.

As described above, traditional mechanical means of anti-aeration and/orminimizing aeration have not been found to be successful due to the highviscosity of the pharmaceutical suspension. For example, applying avacuum to the pharmaceutical suspension can cause a height of thesuspension to rise because the viscous suspension “holds onto” theentrained air. Volatile formulation components may also be lost duringvacuum processing. Further, traditional anti-aerating agents, such asethanol or simethicone emulsion are similarly ineffective atanti-aerating the suspension.

Accordingly, it has been discovered that some chemical compounds, and inparticular, liquid flavors comprising terpenes and/or terpinols such aslimonene, can minimize the aeration of the pharmaceutical suspensionwhen hydrophobic coated Ibuprofen are mixed in to the matrixsolution/suspension. By minimizing aeration, the hydrophobic coatedIbuprofen are more efficiently and effectively dispersed throughout thepharmaceutical suspension. This increased dispersion can increase thehomogeneity of the pharmaceutical suspension, the dose weight accuracy,as well as the content uniformity of the finished product.

As described above, mixing hydrophobic coated Ibuprofen into a matrixsolution/suspension can generate entrained air, or air bubbles in theliquid. Because the coated Ibuprofen are hydrophobic, they have agenerally low affinity for the matrix solution/suspension. Thus, insteadof readily associating with and dispersing into the matrixsolution/suspension, the hydrophobic coated Ibuprofen preferablyassociate with the entrained air. In many fluids, air bubbles typicallytravel to the surface of the fluid and disappear into the air above.However, because the hydrophobic coated Ibuprofen have an affinity forthe entrained air, the hydrophobic coated Ibuprofen “hold onto” the airbubbles, preventing them from traveling to the surface and releasinginto the air above the fluid. This causes the pharmaceutical suspensionto become aerated. Aeration of the pharmaceutical suspension can causephase separation, and thus, a non-homogeneous suspension. The phaseseparation can also become exaggerated upon exposure to shear forcesintroduced by dosing pumps. Non-homogenous pharmaceutical suspensionscan cause pump seizures when passed through dosing pumps, leading toinaccurate dose weights and a lack of uniformity throughout the finishedproduct as well as poor production efficiency through stoppages.

Additionally, pharmaceutical suspensions comprising hydrophobic coatedIbuprofen can have high viscosities due to a high loading of hydrophobiccoated Ibuprofen (i.e., as much as 50 wt. % hydrophobic coatedIbuprofen). Entraining air into the pharmaceutical suspension duringin-line mixing of the hydrophobic coated Ibuprofen into suspension, asdescribed above, can increase the viscosity of the pharmaceuticalsuspension even further. Accordingly, not only does the phase separationand non-homogeneity of the suspension adversely impact the dose weightaccuracy and uniformity of the final product, but so too does theincreased viscosity.

Interestingly, it has been found that certain chemical compounds, whenadded to the matrix solution/suspension, can minimize the aeration ofpharmaceutical suspensions comprising hydrophobic coated Ibuprofen.Particularly, chemical compounds comprising terpene and/or terpinol,according to some embodiments provided herein, may minimize the amountof the entrained air in pharmaceutical suspensions caused by in-linemixing of hydrophobic coated Ibuprofen into matrixsolutions/suspensions. For example, suspensions comprising liquidflavors comprising terpenes and/or terpinols, even in relatively lowconcentrations, can minimize aeration of pharmaceutical suspensions.Specifically, it has been discovered that matrix solutions/suspensionscomprising one or more liquid flavor comprising limonene can minimizeaeration in pharmaceutical suspensions during in-line mixing ofhydrophobic coated Ibuprofen. Other chemical compounds includingterpenes and terpinols have been shown to be successful at minimizingaeration of pharmaceutical suspensions as well. For example, chemicalcompounds including terpenes such as limonene, carvone, humulene,taxadiene, and squalene may be suitable for minimizing the aeration ofthe pharmaceutical suspension. Terpinol may also be a suitableanti-aerating agent. In some embodiments, pure terpenes and/or pureterpinols may be used as an anti-aerating agent. In some embodiments, aliquid flavor comprising terpene and/or terpinol may be used as ananti-aerating agent. In some embodiments, other suitable chemicalcompounds comprising terpene and/or terpinol may be used as ananti-aerating agent.

One challenge posed with some chemical compounds comprising terpeneand/or terpinol, such as some liquid flavors, is that they tend to berelatively oily. As with conventional oil and water, these oily chemicalcompounds may not readily disperse into a matrix solution/suspension.However, as discussed below, matrix solutions/suspensions according toembodiments here may include gelatin as a matrix former. Gelatin isinherently a mild surfactant. Surfactants can lower the surface tensionbetween two materials. Accordingly, in some embodiments, the gelatin ofthe matrix solution/suspension can reduce the surface tension betweenthe oily chemical compounds and the matrix solution/suspension. This canallow adequate incorporation of the oily chemical compounds, such asliquid flavors, into the matrix solution/suspension.

Under normal processing conditions, without use of chemical compoundscomprising terpene and/or terpinol, the coating of the hydrophobiccoated Ibuprofen erodes with time due to shear forces required to mixthe hydrophobic coated Ibuprofen into the matrix solution/suspension toform the pharmaceutical suspension. However, there is a “processingwindow” of two or more hours wherein the coating retains significantfunctionality. The exact time of this “processing window” varies foreach product, and can depend upon the composition of the components ofthe hydrophobic coated Ibuprofen, the composition of the matrixsolution/suspension, the amount of material used to prepare thehydrophobic coated Ibuprofen, the physicochemical properties ofIbuprofen, and/or the conditions of mixing. Unfortunately, in thepresence of chemical compounds comprising terpenes and/or terpinols this“processing window” can be significantly reduced due to interactionsbetween these chemical compounds and the coating of the hydrophobiccoated Ibuprofen. These interactions may damage the functionalproperties of the coating. For example, interactions between liquidflavors and the coating of the hydrophobic coated Ibuprofen may damageany taste-masking functionality of the coating. That said, it has beendiscovered that there is a threshold chemical compounds (i.e., liquidflavor) concentration below which the chemical compound does notsignificantly compromise the coating, yet the “processing window” is notreduced so much that the coating of the hydrophobic coated Ibuprofensignificantly erodes. Accordingly, this optimal amount of chemicalcompound comprising terpene and/or terpinol adequately minimizes theaeration of the pharmaceutical suspension, resulting in a homogenouspharmaceutical suspension that can be accurately dosed into molds toyield a uniform final product.

Additionally, chemical compounds comprising terpene and/or terpinol, andspecifically liquid flavors comprising limonene, have the potential tolower the freezing point of the pharmaceutical suspension, which couldlead to melting defects for products further processed by freeze-drying.In particular, limonene has a freezing point of −74° C. However, nomelting defects have been observed during the preparation of thedisclosed product, and thus at least some chemical compounds comprisingterpene and/or terpinol do not impact the pharmaceutical suspension suchthat the freezing and freeze-drying process steps downstream areadversely affected. The absence of melting defects under the presentcircumstances is believed to be due to the high solids content of thesuspension, which helps to maintain the structure of the product, evenin the presence of a freezing point depressing agent (i.e., limonene).

Matrix solution/suspension compositions according to embodimentsdescribed herein may include a matrix former, a structure former, ananti-aerating agent, a viscosity modifier, and/or a solvent.

In some embodiments, an amount of a chemical compounds comprisingterpene and/or terpinol (i.e., an anti-aerating agent) in the matrixsolution/suspension, the pharmaceutical suspension, or thepharmaceutical composition may be from 0.001 to 5.0% w/w. In someembodiments, an amount of chemical compounds comprising terpene and/orterpinol (i.e., an anti-aerating agent) in the matrixsolution/suspension, the pharmaceutical suspension, or thepharmaceutical composition can be 1-5% w/w, 1-4% w/w, 1-3% w/w, 1-2%w/w, 0.05 to 3.0% w/w, 0.1 to 2.0% w/w, or 0.5 to 1.0% w/w. In someembodiments, more than 0.001% w/w, more than 0.01% w/w, more than 0.05%w/w, more than 0.1% w/w, more than 0.3% w/w, more than 0.5% w/w, morethan 0.8% w/w, more than 1.0% w/w, more than 1.5% w/w, more than 2.0%w/w, more than 2.5% w/w, more than 3.0% w/w, more than 3.5% w/w, morethan 4.0% w/w, or more than 4.5% w/w of chemical compounds comprisingterpene and/or terpinol (i.e., an anti-aerating agent) are in the matrixsolution/suspension, the pharmaceutical suspension, or thepharmaceutical composition. In some embodiments, less than 5.0% w/w,less than 4.5% w/w, less than 4.0% w/w, less than 3.5% w/w, less than3.0% w/w, less than 2.5% w/w, less than 2.0% w/w, less than 1.5% w/w,less than 1.0% w/w, less than 0.8% w/w, less than 0.6% w/w, less than0.3% w/w, or less than 0.1% w/w of chemical compounds comprising terpeneand/or terpinol (i.e., an anti-aerating agent) are in the matrixsolution/suspension, the pharmaceutical suspension, or thepharmaceutical composition. In some embodiments, a suitableanti-aerating agent may include orange flavor, strawberry flavor, mintflavor, raspberry flavor, licorice flavor, orange flavor, lemon flavor,lime flavor, grapefruit flavor, caramel flavor, vanilla flavor, cherryflavor, grape flavor, mixed fruit flavor, tutti-frutti flavor or anycombination thereof.

Minimizing Agglomeration Examples

Several trials were performed to evaluate the effectiveness of removingexcess coating material from coated Ibuprofen by sieving and to optimizethe coating ratios and dosing ratios. Disintegration times ofpharmaceutical compositions containing various coated Ibuprofen weremeasured under various conditions to study the effect of sieving excesscoating material. It may be reasonably assumed that removing excesscoating material can minimize agglomeration of the coating material.Optimizing the coating and dosing ratios can also aid in minimizingcoating material agglomeration. In turn, minimizing the amount ofagglomeration can help maintain desired disintegration times and/ordissolution rates of the pharmaceutical composition and coatedIbuprofen. Accordingly, disintegration time is used as a metric toevaluate the amount of agglomeration in the following Examples. In someembodiments, the 50° C. accelerated disintegration data can beindicative of the presence of unsieved, excess coating material.

Additionally, coating ratio and dosing ratio information is provided forthe Examples below. Coating ratio refers to the amount of coatingmaterials to the amount of uncoated Ibuprofen. Dosing ratio refers tothe amount of coated Ibuprofen to the matrix solution/suspensioncomprising of all the inactive ingredients.

Example 1: Ibuprofen was coated with carnauba wax with a coating ratioof 26:74. A dosing ratio of 40:60 was used to produce freeze driedtablets. Four separate batches of tablets were tested—Batch 1-3 over aperiod of 2 months, and Batch 4 over a period of 6 months. These batchesof tablets were each tested at ICH (International Council forHarmonisation of Technical Requirements for Pharmaceuticals for HumanUse) stability conditions of 25° C./60% RH, 30° C./65% RH, and 40°C./75% RH and sampled at one month and two months for Batches 1, 2, and3. Additionally, each batch was exposed to a 50° C. stress condition toprovide accelerated data at both two weeks and at four weeks for eachstudy. Table 1 below provides the disintegration time data for Batches1-3 of the two-month study of coated ibuprofen.

TABLE 1 Carnauba Wax (Dosing Ratio 40:60) (2-Month Study) 1 1 1 2 2 2 24 Month Month Month Month Month Month Batch Initial Week Week 25° C./30° C./ 40° C./ 25° C./ 30° C./ 40° C./ Batch Nos Strength DT 50° C. 50°C. 60% RH 65% RH 75% RH 60% RH 65% RH 75% RH 1 Z3876/128 400 MG  <2 s <4s <10 s  <4 s <4 s <4 s <3 s <4 s <7 s 2 Z4630/97 50 MG <2 s <4 s <7 s<2 s <2 s <2 s <2 s <2 s <15 s  3 Z4630/101 50 MG <3 s <3 s <4 s <1 s <2s <3 s <2 s <2 s <2 s

Coated Ibuprofen for Batch 2 was poorly sieved post Ibuprofen coating.Microscopic examination (FIG. 4B) of the sieved coated Ibuprofen showedthe presence of an excess amount of unbound coating material.Microscopic examination of the sieved coated Ibuprofen also showed thatthe Ibuprofen was poorly coated. As shown in the last column of Table 1,this batch exhibited a significantly longer disintegration time at the40° C./75% RH stability testing conditions after two-months. (Theinitial disintegration time was less than two seconds, and thedisintegration time at two months was almost 15 seconds). Accordingly,this result supports the hypothesis that presence of an excess amount ofunbound coating material in the pharmaceutical product is responsiblefor extended disintegration time over time (as the pharmaceuticalproduct ages) because of the agglomeration of the unbound coatingmaterial during storage.

Conversely, coated Ibuprofen for Batch 3 was sieved well post Ibuprofencoating. Microscopic examination (FIG. 4C) of the sieved coatedIbuprofen showed that the Ibuprofen was well coated since there is anabsence of unbound coating material. The disintegration time for thesamples of this batch changed very little over the two-month period forany of the ICH stability conditions. (The disintegration time throughoutthe two-month study fluctuated between approximately one second andapproximately three seconds). This supports the hypothesis thatminimizing the presence of excess unbound coating material by sieving,for example, will help to prevent the agglomeration of coating materialin pharmaceutical product when place on storage, particularly at highertemperatures over time.

The coated Ibuprofen for Batch 1 was sieved post Ibuprofen coating.Batch 1 exhibited similar disintegration time of less than 2 secondscompared to Batch 2 and 3 for the initial time data points. However, atthe 40C/75% RH stability testing conditions after two-months, thedisintegration time increased to approximately 7 seconds or less. Whenstored for 4 weeks at 50° C., the disintegration time increased toapproximately 10 seconds or less. This suggests that the sieving processfor this batch did not sufficiently remove the excess coating material,hence the presence of residual unbound coating material. Batch 2experienced even more unbound coating material and agglomeration onstorage to a greater extent than that of Batch 1. Microscopicexamination (FIG. 4A) of the sieved coated Ibuprofen showed that theIbuprofen particles were moderately well coated with residue amount ofunbound coating material present.

Table 2 below shows the disintegration time data for the six-month studyof coated Ibuprofen (i.e., Batch 4).

TABLE 2 Carnauba Wax (Dosing Ratio 40:60) (6-Month Study) 1 1 1 2 4Month Month Month Batch Week Week 25° C./ 30° C./ 40° C./ Batch NosStrength Initial 50° C. 50° C. 60% RH 65% RH 75% RH 4 Z3876/131 200 MG<5 s <20 s <13 s <5 s <4 s <5 s 3 3 3 6 6 6 Month Month Month MonthMonth Month 25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ Batch 60% RH65% RH 75% RH 60% RH 65% RH 75% RH 4 <4 s <3 s <4 s <2 s <2 s <2 s

The coated Ibuprofen for Batch 4 was sieved post Ibuprofen coating.Batch 4 of Table 2 did not show much change in disintegration timethroughout the duration of the six-month study. The initialdisintegration time of Batch 4 was approximately five seconds, and thefinal disintegration time of the 25° C./60% RH samples was approximatelytwo seconds; the 30° C./65% RH samples approximately two seconds, andthe 40° C./75% RH samples approximately two seconds. However, anincrease was seen when stored at 50° C. Since no increase was seen inthe tablets stored at temperatures of 40° C. and below, this suggeststhat sieving has removed most of the unbound excess coating material butwith sufficient residue amount that agglomerate when the tablets wereplaced at 50° C. Microscopic examination (FIG. 4D) showed that thesieved coated Ibuprofen showed that the Ibuprofen were moderately wellcoated with residue amount of unbound coating material present.

Example 2: Ibuprofen was coated with Sasol (synthetic) wax with atheoretical coating ratio of 26:74. The coated Ibuprofen was sievedafter coating. A dosing ratio of 40:60 was used to produce freeze driedtablets and tested over two months. The Ibuprofen strength was 200 mg.Each batch was tested at ICH stability conditions of 25° C./60% RH, 30°C./65% RH, and 40° C./75% RH. Additionally, the samples were exposed toa 50° C. stress condition to provide accelerated data at two weeks andat four weeks during the study. Table 3 below provides thedisintegration time data for the 40:60 dosing ratio two month study ofcoated Ibuprofen. Microscopic examination (FIG. 4E) of the sieved coatedIbuprofen showed that the Ibuprofen were moderately well coated with asmall amount of unbound coating material.

TABLE 3 Sasol Wax (Dosing Ratio 40:60) Ibuprofen Strength: 200 mg 1 1 12 2 2 2 4 Month Month Month Month Month Month Batch Initial Week Week25° C./ 30° C./ 40° C./ 25° C./ 30° C./ 40° C./ Batch Nps DT 50° C. 50°C. 60% RH 65% RH 75% RH 60% RH 65% RH 75% RH 5 Z3876/138 <3 s <3 s <4 s<2 s <2 s <5 s <4 s <4 s <4 s

Batch 5 of Table 3 shows no substantial change in the disintegrationtime during the two months of the study, nor at the 50° C. acceleratedconditions. Specifically, the initial disintegration time of Batch 5 wasapproximately three seconds, and the disintegration time at two monthsfor all three ICH stability conditions (25° C./60% RH, 30° C./65% RH,and 40° C./75% RH) was approximately four seconds. The disintegrationtime for the 50° C. accelerated condition at two weeks was approximatelythree seconds and at 4 weeks was approximately four seconds. Based onthe 50° C. data, a small residue amount of unbound excess coatingmaterial may be present. If so, this small amount of unbound excesscoating material does not cause a significant amount of agglomeration onstorage, since the disintegration time does not increase much, if atall. This compares well with Batch 3 in Example 1 where a different waxwas used. These 2 examples demonstrate that if the unbound excesscoating material is efficiency removed by sieving, agglomeration of thecoating material in the pharmaceutical product on storage can beminimized or prevented, in particular at higher temperatures and uponprolonged storage period.

Example 3: Ibuprofen was coated with Sasol (synthetic) wax with atheoretical coating ratio of 26:74. The coated ibuprofen was then sievedafter coating. A dosing ratio of 50:50 was used to produce freeze driedtablets and tested over three months. The Ibuprofen strength was 200 mg.As above in Examples 1 and 2, each batch was tested at ICH stabilityconditions of 25° C./60% RH, 30° C./65% RH, and 40° C./75% RH. Thesamples were also exposed to a 50° C. stress condition to provideaccelerated data at two weeks and at four weeks during each study. Table4, below, provides data for the three-month study of 50:50 Sasolwax-coated Ibuprofen. Microscopic examination (FIG. 4F) of the sievedcoated API for Batch 6 showed the Ibuprofen were coated well and withsome unbound coating material.

TABLE 4 Sasol Wax (Dosing Ratio 50:50) Ibuprofen Strength: 200 mg 1 1 24 1 Month Month Batch Initial Week Week Month 30° C./ 40° C./ Batch NosDT 50° C. 50° C. 25° C./60% 65% RH 75% RH 6 Z3876/142 <1 s <2 s <2 s <2s <2 s <2 s 7 Z3876/141/1 <2 s <5 s <5 s <2 s <3 s <3 s 2 2 2 3 3 3Month Month Month Month Month Month 25° C./ 30° C./ 40° C./ 25° C./ 30°C./ 40° C./ Batch 60% RH 65% RH 75% RH 60% RH 65% RH 75% RH 6 <2 s <1 s<2 s <2 s <2 s <2 s 7 <2 s <2 s <3 s <2 s <2 s <3 s

Neither Batch 6 nor Batch 7 showed significant change in disintegrationtime over the course of the three month study. Specifically, the initialdisintegration time of the samples of Batch 6 was approximately onesecond, and the final three-month disintegration time for each of thethree ICH stability conditions (25° C./60% RH, 30° C./65% RH, and 40°C./75% RH) was approximately two seconds. The disintegration time forboth the two-week and the four-week accelerated 50° C. condition forBatch 6 was approximately two seconds.

The initial disintegration time for the samples of Batch 7 wasapproximately two seconds, and the final three-month disintegration timefor the 25° C./60% RH and 30° C./65% RH ICH stability conditions wasapproximately two seconds. The final three-month disintegration time forthe 40° C./75% RH ICH stability condition was approximately threeseconds. The disintegration time for both the two-week and the four-weekaccelerated 50° C. condition was approximately five seconds. A highcoating ratio of 50:50 can increase the amount of excess unbound coatingmaterial when left unsieved. Although both batches used a higher dosingratio of 50:50, which means a high loading of the coated Ibuprofen andany unbound excess coating material, these data inferred that thesieving process of the coated Ibuprofen has been effective in removingthe unbound excess coating materials to minimize agglomeration.

Example 4: Ibuprofen was coated with Carnuba Wax at a theoreticalcoating ratio of 22.5:77.5 and 30:70. A dosing ratio of 30:70 was usedto produce freeze dried tablets and study over a period of 2 months. TheIbuprofen strength was 200 mg. The batches were stored in an oven at 40°C. Tablets were tested for disintegration time at the initial, Day 25,and 2 month time points. Table 5 below provides the disintegration timesfor the study. Microscopic examination of the unsieved coated Ibuprofen(FIGS. 4G and 4H) and sieved coated Ibuprofen (FIGS. 41 and 4J). TheIbuprofen were well coated. Sieved samples have no unbound coatingmaterial present.

TABLE 5 Carnuba Wax (Dosing Ratio 30:70) Ibuprofen Strength: 200 mg BachCoating Day 24 2 Month Batch Nps Coated API Ratio Initial At 40° C. At40° C. 8 Z4750/186/2a Unsieved 22.5:77.5 5 s 2 s 2 s 9 Z4750/186/4aSieved 22.5:77.5 4 s 3 s 3 s 10 Z4750/186/6a Unsieved 30:70 1 s 2 s 2 s11 Z4750/186/8a Sieved 30:70 2 s 3 s 3 s

Batch 8-11 show that using a dosing ratio of 30:70 for coated Ibuprofen,either unsieved (Batches 8 and 10) or sieved (Batches 9 and 11), thedisintegration times of the tablets stored at 40° C. has not increasedover time. This supports the hypothesis that by reducing the dosingratio; such as to 30:70, the amount of excess unbound wax issufficiently reduced to a level that can minimize agglomeration of theexcess unbound material when stored at higher temperatures over time.

The overall summary of results from the above examples are tabulated theTable 6.

TABLE 6 Overall Summary of Results for Batches 1-11. DisintegrationSieving Time at Disintegration of Coating Unbounded 40′ C./75% time atBatch Strength Coating Dosing Coated Assessment Excess Wax RH at 50′ C.at Batch Nos Drug (mg) Ratio Ratio API (Microscopy) (Microscopy) 1/2/3/6mths 2/4 wk 1 Z3876/128 Ibuprofen 400 26:74 40:60 Sieved ModeratePresent <4-7 s  <4-10 s  2 Z4630/97 Ibuprofen 50 26:74 40:60 Sieved PoorPresent <2-15 s    <4-7 s (poor) 3 Z4630/101 Ibuprofen 50 26:74 40:60Sieved Good Absent <2-3 s  <3-4 s (well) 4 Z3876/131 Ibuprofen 200 26:7440:60 Sieved Moderate Present <2-5 s  <13-20 s  5 Z3876/138 Ibuprofen200 26:74 40:60 Sieved Good Present <4-5 s  <3-4 s 6 Z3876/142 Ibuprofen200 26:74 50:50 Sieved Good Present <2 s  <2 s 7 Z3876/141/1 Ibuprofen200 25:75 50:50 Sieved No Photo No Photo <3 s  <5 s 8 Z4750/186/2aIbuprofen 200 22.5:77.5 30:70 Unsieved Good Present <2 s No data 9Z4750/186/4a Ibuprofen 200 22.5:77.5 30:70 Sieved Good Absent <3 s Nodata (well) 10 Z4750/186/6a Ibuprofen 200 30:70 30:70 Unsieved GoodPresent <2 s No data 11 Z4750/186/8a Ibuprofen 200 30:70 30:70 SievedGood Absent <3 s No data

Preserving Functionally-Coated Ibuprofen Examples

Example 5: Hydrophobic fumed silica was used to coat functionally-coatedIbuprofen according to embodiments described herein. Specifically, thehydrophobic fumed silica that was used was Aerosil R972 (“Aerosil”). Twodifferent concentrations of Aerosil R972 were tested-1.5% w/w and 1.0% %w/w. The size of the functionally-coated Ibuprofen were evaluated over a6-hour holding period, during which they were subjected to low shearmixing.

FIGS. 5, 6, and 7 provide evaluations of d10 particle size, d50 particlesize, and d90 particle size, respectively, over a period of 6 hours.Generally speaking, a particle size expressed in terms of its d10 meansthat 10 percent of the particles in a given amount of sample lie below agiven particle size. Accordingly, a particle size expressed in terms ofits d50 means that 50 percent of the particles in a given amount ofsample lie below a given particle size, and a particle size expressed interms of its d90 means that 90 percent of the particles in a givenamount of sample lie below a given particle size.

As shown in FIG. 5, the greater concentration of silica (1.5% w/w) wasmore effective at maintaining the original particle size, and thusmaintaining the coating, than the lesser concentration of silica (1.0%w/w). Specifically, during the 6-hour period, the functionally-coatedIbuprofen comprising 1.5% w/w Aerosil lost approximately 30% of theiroriginal size, whereas the functionally-coated Ibuprofen comprising 1.0%w/w Aerosil lost approximately 80% of their original particle size.

FIG. 6 demonstrates that again the greater concentration of silica (1.5%w/w Aerosil) was more effective at maintaining the originalfunctionally-coated Ibuprofen particle size, and thus preserving thefunctional coating, than the lesser concentration of silica (1.0% w/wAerosil). Specifically, during a period of 6 hours, thefunctionally-coated Ibuprofen comprising 1.5% w/w Aerosil lost almost20% of their original size, whereas the functionally-coated Ibuprofencomprising 1.0% w/w Aerosil lost approximately 45% of their originalfunctionally-coated API particle size.

FIG. 7 also shows that the greater concentration of silica (1.5% w/wAerosil) was more effective at maintaining the originalfunctionally-coated Ibuprofen particle size, and thus preserving thefunctional coating of the functionally-coated Ibuprofen, than the lesserconcentration of silica (1.0% w/w Aerosil). Specifically, during the6-hour period, the functionally-coated Ibuprofen comprising 1.5% w/wAerosil lost almost 15% of their original size, whereas thefunctionally-coated Ibuprofen comprising 1.0% w/w Aerosil lostapproximately 35% of their original particle size.

Additionally, as the particle size of the functionally-coated Ibuprofendecreased, a separate population of particles comprising a particle sizeof 5 μm to 20 μm appeared and increased with time. These particles arebelieved to be non-deformable coating material particles embedded withinthe deformed, continuous coating material prior to erosion of thecoating due to shear forces. Accordingly, as the coating erodes, and theparticle size of the functionally-coated Ibuprofen decreases, thepopulation size of these smaller particles increases as the deformedcoating material surrounding them erodes, causing these non-deformableparticles to release from the functionally-coated Ibuprofen.

Overall, these trials suggest that 1.5% w/w Aerosil coating thefunctionally-coated Ibuprofen may increase the “processing window” toapproximately 4 hours, instead of the 2 hour “processing window” thatexists without the silica. Within the first four hours of processing insuspension and comprising a second, outer coating comprising 1.5% w/wAerosil, the functionally-coated Ibuprofen exhibit little, if any,erosion of the coating.

Example 6: Hydrophobic fumed silica was used to coat functionally-coatedIbuprofen according to embodiments described herein. Specifically, thehydrophobic fumed silica that was used was Aerosil R972 (“Aerosil”).Five different concentrations of Aerosil R972 were tested-0.0% w/w, 1.5%w/w, 2.5% w/w, 5.0% w/w and 10.0% w/w. The release amount of thefunctionally coated Ibuprofen was evaluated using dissolution testing(i.e., dissolution media of 0.01% SDS in pH 7.2 phosphate buffer, mediatemperature of 37° C., and media volume of 10 ml (Ibuprofen)).

FIGS. 8 and 9 provide evaluations of release amount conducted on thefunctionally coated Ibuprofen, over a period of either 5 or 30 minutes.Generally speaking, a low volume dissolution result expressed in termsof its % release means that ‘x’ percent of the weight of material addedhas dissolved into solution.

FIG. 8 shows release data for Ibuprofen coated with carnauba wax andvarious amounts of hydrophobic silica. As shown in the Figure, greaterconcentrations of silica (up to 10.0% w/w) were more effective atproviding a slower release rate in dissolution testing, and thusmaintaining the coating, than the lesser concentrations of silica.Specifically, during the 5 minute testing period, thefunctionally-coated Ibuprofen (i.e., Ibuprofen coated with carnauba wax)comprising 10.0% w/w Aerosil exhibited a 1.5% release after 5 minutes,whereas the functionally-coated Ibuprofen comprising 0.0% w/w Aerosilexhibited a 24.9% release. Functionally-coated Ibuprofen comprisingintermediate levels of Aerosil (i.e., 1.5% w/w, 2.5% w/w and 5.0% w/w)showed dissolution results after 5 minutes of 12.1% release, 7.4%release and 2.3% release, respectively.

FIG. 9 provides release data for Ibuprofen coated with Sasol (synthetic)wax and various levels of hydrophobic silica. FIG. 10 also shows thatgreater concentrations of silica (up to 10.0% w/w) were more effectiveat providing a slower release rate in dissolution testing, and thusmaintaining the coating, than the lesser concentrations of silica.Specifically, during the 5 minute testing period, thefunctionally-coated Ibuprofen (i.e., Ibuprofen coated with syntheticwax) comprising 10.0% w/w Aerosil exhibited a 2.8% release after 5minutes, whereas the functionally-coated Ibuprofen comprising 0.0% w/wAerosil shows an 8.5% release. Functionally-coated Ibuprofen comprisingintermediate levels of Aerosil (i.e., 1.5% w/w, 2.5% w/w and 5.0% w/w)gave dissolution results after 5 minutes of 4.3% release, 3.6% releaseand 2.4% release, respectively.

Minimizing Aeration Examples

The effectiveness of chemical compounds comprising terpene and/orterpinol at minimizing aeration can be determined in part by measuringthe particle size of the hydrophobic coated Ibuprofen in pharmaceuticalsuspension over time. If the chemical compound is effective, theaeration of the suspension will be adequately low and the particle sizeof the hydrophobic coated Ibuprofen will remain constant or decreasevery little over time. If ineffective, the aeration of the suspensionwill be higher than desired and the particle size of the hydrophobiccoated Ibuprofen can decrease more substantially over time. The extentof aeration of the suspension is assessed by measurement of height ofthe foam in the mixing vessel. The particle size of thefunctionally-coated particles can be measured using laser diffraction, aparticle analyzer such as a Malvern Mastersizer, or any other suitablemeans for analyzing fine particles.

Example 7: A series of suspension mixes were manufactured by mixing thecoated Ibuprofen in the matrix solution/suspension containing variouslevels of limonene, orange flavor, and strawberry flavor. The height ofthe foam from these suspension is summarized in Table 7, 8, and 9respectively.

TABLE 7 Height of foam from mixes containing various levels of limonene.Concentration of limonene (% w/w) Foam Height (mm) 0 5 0.15 2 0.30 1 0.61

TABLE 8 Height of foam from mixes containing various levels of orangeflavor. Concentration of orange flavor (% w/w) Foam Height (mm) 0 5 0.151 0.30 0 0.6 0

TABLE 9 Height of foam from mixes containing various levels ofstrawberry flavor. Concentration of strawberry flavor (% w/w) FoamHeight (mm) 0 5 0.15 3 0.30 3 0.6 3

The results in Tables 7 and 8 show that the addition of limonene andorange flavor at level 0.15% w/w and above minimize the aeration. Forstrawberry (Table 9), it also reduced aeration but not to the sameextent.

Example 8: FIGS. 10, 11, and 12 show the decrease in particle size (d10,d50, and d90, respectively) of hydrophobic coated Ibuprofen in apharmaceutical suspension comprising various concentrations of liquidorange flavor. A particle size expressed in terms of its d10 means that10 percent of the particles in a given volume of sample lie below agiven particle size. Accordingly, a d50 particle size represents 50percent of the particles in a given volume of sample lie below a givenparticle size, and a d90 particle size represents 90 percent of theparticles in a given volume of sample lie below a given particle size.Specifically, FIGS. 3-5 show test results for suspension formulationscontaining hydrophobic coated Ibuprofen and liquid orange flavor atconcentrations including 0.0%, 0.15%, 0.45%, and 0.60% w/w, held over aperiod of up to 6 hours with low shear mixing.

At concentrations of up to 0.45% w/w of orange flavor (including 0.15%w/w), the decrease in d10, d50, and d90 particle size within the first 2hour “processing window” is largely similar to that of a pharmaceuticalsuspension comprising hydrophobic coated Ibuprofen without any liquidflavor (0% liquid flavor). However, at a concentration of 0.6% w/wliquid orange flavor, the coating of the hydrophobic coated Ibuprofen isreadily removed and a rapid decrease in particle size is observed.Further, at a liquid orange flavor concentration of 0.3% w/w, theaeration of the suspension was sufficiently low with only little, if anydamage to the coating of the coated ibuprofen, and only minimal decreasein particle size of the hydrophobic coated Ibuprofen.

Example 9: FIGS. 13, 14, and 15 provide data on the decrease in d10,d50, and d90 particle size, respectively, of the hydrophobic coatedIbuprofen for the specific component limonene, which is found in someliquid flavors. These tests were conducted to explore the behaviors ofthe specific component of the liquid flavor, limonene, on hydrophobiccoated Ibuprofen in suspension. Note that the concentrations of limoneneshown in the Figures are significantly greater than the concentration oflimonene that would be present if a liquid flavor was used. In FIGS.13-15, pure limonene was used in concentrations of 0.25% w/w, 0.45% w/w,and 0.75% w/w and tested over a period of 24 hours. As shown across allthree Figures, a limonene concentration of 0.25% w/w had a much lessdeleterious effect on the coating of the hydrophobic coated Ibuprofenparticle size than limonene concentration of 0.45% w/w and 0.75% w/w.Further, the pharmaceutical suspensions tested with 0.25% w/w limonenecomprised a sufficiently low amount of aeration. Accordingly, thesetests confirm that limonene of the liquid orange flavor tested in FIGS.3-5 are at least partially responsible for minimizing the aeration ofthe pharmaceutical suspension and subsequently eroding the coating ofthe hydrophobic coated Ibuprofen in relatively high quantities and/or atrelatively high exposure times.

Example 10: FIG. 16 shows testing data of two different liquidflavors—strawberry and orange. D10, d50, and d90 particle sizes of thehydrophobic coated Ibuprofen were tested for both strawberry liquidflavor and orange liquid flavor. Both strawberry and orange liquidflavors comprise limonene. As shown in the Figure, both flavors behavesimilarly with regards to hydrophobic coated Ibuprofen particle size.The d10 particle samples showed a greater amount of particle sizedecrease within the first two hours of the trial than the d50 and d90particle size samples. The d50 and d90 particle size samples exhibitedless of a particle size decrease within the same two-hour period.However, this observation is consistent with the data of d10, d50, andd90 particle sizes of the previously-discussed examples.

Additionally, it was observed in all trials that as the particle size ofthe hydrophobic coated API (Ibuprofen) particles decreased, a separatepopulation of particles comprising a particle size of 5 μm to 20 μmappeared and increased with time. These particles are believed to benon-deformable coating material particles embedded within the deformed,continuous coating material prior to erosion of the coating due to shearforces. Accordingly, as the coating erodes, and the particle size of thehydrophobic coated Ibuprofen decreases, the population size of thesesmaller particles increases as the deformed coating material surroundingthem erodes, causing these non-deformable particles to release from thehydrophobic coated Ibuprofen.

Overall, these trials show that by optimizing the amount of the terpenelimonene to add to the pharmaceutical suspension comprising hydrophobiccoated Ibuprofen, the amount of aeration in the suspension can beminimized to permit downstream processing while at the same time nothaving an adverse effect on the coating of the hydrophobic coatedIbuprofen (as determined by the particle size of the hydrophobic coatedIbuprofen.)

The foregoing description, for the purpose of explanation, has beendescribed with reference to specific embodiments. However, theillustrative discussions above are not intended to be exhaustive or tolimit the invention to the precise forms disclosed. Many modificationsand variations are possible in view of the above teachings. Theembodiments were chosen and described in order to best explain theprinciples of the techniques and their practical applications. Othersskilled in the art are thereby enabled to best utilize the techniquesand various embodiments with various modifications as are suited to theparticular use contemplated.

Although the disclosure and examples have been fully described withreference to the accompanying figures, it is to be noted that variouschanges and modifications will become apparent to those skilled in theart. Such changes and modifications are to be understood as beingincluded within the scope of the disclosure and examples as defined bythe claims.

1. A coated active pharmaceutical ingredient (“API”) comprising: a firstcoating material surrounding an API; and a second coating materialsurrounding, partially embedded in, and/or embedded in the first coatingmaterial.
 2. The coated API of claim 1, wherein the second coatingmaterial comprises silica.
 3. The coated API of claim 2, wherein thecoated API comprises 0.5-10% w/w silica.
 4. The coated API of claim 1,wherein the first coating material comprises 10-30% w/w of the coatedAPI.
 5. The coated API of claim 1, wherein the first coating materialcomprises a wax.
 6. The coated API of claim 5, wherein the first coatingmaterial comprises one or more of carnauba wax, synthetic wax, orcandelilla wax.
 7. The coated API of claim 1, wherein the API comprisesIbuprofen.
 8. The coated API of claim 1, wherein the coated API has alow volume 60 minute dissolution test result less than or equal to 70%after 15 minutes.
 9. A method of preparing a coated activepharmaceutical ingredient (“API”): mixing API particles with a firstcoating material comprising one or more deformable components; exposingthe mixture of API particles and first coating material to mechanicaland thermal energy to deform the one or more deformable components andform coated API particles; mixing the coated API particles with a secondcoating material; exposing the mixture of coated API particles andsecond coating material to mechanical and thermal energy to at least oneof surround, partially embed, or embed the second coating material onthe coated API particles; and sieving the coated API particlescomprising the second coating material to remove excess coating materialnot bound to the coated API particles comprising the second coatingmaterial.
 10. The method of claim 9, further comprising sieving uncoatedAPI particles.
 11. The method of claim 9, wherein sieving the coated APIparticles comprising the second coating material comprises passing thecoated API particles comprising the second coating material through adevice comprising two or more sieves.
 12. The method of claim 9, whereinsieving the coated API particles comprising the second coating materialcomprises sieving the coated API particles comprising the second coatingmaterial to an average particle size of 75-250 μm.
 13. The method ofclaim 9, wherein the API particles comprise one or more ofanti-inflammatories, analgesics, anti-psychotics, anti-emetics,laxatives, anti-diarrheals, anti-histamines, or anti-depressants. 14.The method of claim 13, wherein the API particles comprise Ibuprofen.15. The method of claim 9, wherein the one or more deformable componentsof the first coating material comprises a wax.
 16. The method of claim15, wherein the wax comprises one or more of carnauba wax, candelillawax, or synthetic wax.
 17. The method of claim 9, wherein the secondcoating material comprises silica.
 18. The method of claim 17, whereinthe coated API particles comprising the second coating materialcomprises 0.5-10% w/w silica.
 19. The method of claim 9, wherein thecoated API particles comprising the second coating material comprises10-30% w/w the first coating material.
 20. The method of claim 9,wherein the coated API has a low volume 60 minute dissolution testresult less than or equal to 70% after 15 minutes.